Tetrazole-substituted arylamides as p2x3 and p2x2/3 antagonists

ABSTRACT

Compounds of the formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein, R 1  is optionally substituted tetrazolyl, R 2  is optionally substituted phenyl, optionally substituted pyridinyl or optionally substituted thienyl, and R 3 , R 4 , R 5  and R 6  are as defined herein. Also provided are methods of using the compounds for treating diseases associated with the P2X 3  and/or a P2X 2/3  receptor antagonist and methods of making the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/817,298 filed Jun. 29, 2006, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention pertains to compounds useful for treatment of diseasesassociated with P2X purinergic receptors, and more particularly to P2X₃and/or P2X_(2/3) antagonists usable for treatment of genitourinary,pain, gastrointestinal and respiratory diseases, conditions anddisorders.

BACKGROUND OF THE INVENTION

The urinary bladder is responsible for two important physiologicalfunctions: urine storage and urine emptying. This process involves twomain steps: (1) the bladder fills progressively until the tension in itswalls rises above a threshold level; and (2) a nervous reflex, calledthe micturition reflex, occurs that empties the bladder or, if thisfails, at least causes a conscious desire to urinate. Although themicturition reflex is an autonomic spinal cord reflex, it can also beinhibited or mediated by centers in the cerebral cortex or brain.

Purines, acting via extracellular purinoreceptors, have been implicatedas having a variety of physiological and pathological roles. (See,Burnstock (1993) Drug Dev. Res. 28:195-206.) ATP, and to a lesserextent, adenosine, can stimulate sensory nerve endings resulting inintense pain and a pronounced increase in sensory nerve discharge. ATPreceptors have been classified into two major families, the P2Y- andP2X-purinoreceptors, on the basis of molecular structure, transductionmechanisms, and pharmacological characterization. TheP2Y-purinoreceptors are G-protein coupled receptors, while theP2X-purinoreceptors are a family of ATP-gated cation channels.Purinergic receptors, in particular, P2X receptors, are known to formhomomultimers or heteromultimers. To date, cDNAs for several P2Xreceptors subtypes have been cloned, including: six homomeric receptors,P2X₁; P2X₂; P2X₃; P2X₄; P2X₅; and P2X₇; and three heteromeric receptorsP2X_(2/3), P2X_(4/6), P2X_(1/5) (See, e.g., Chen, et al. (1995) Nature377:428-431; Lewis, et al. (1995) Nature 377:432-435; and Burnstock(1997) Neurophamacol. 36:1127-1139). The structure and chromosomalmapping of mouse genomic P2X₃ receptor subunit has also been described(Souslova, et al. (1997) Gene 195:101-111). In vitro, co-expression ofP2X₂ and P2X₃ receptor subunits is necessary to produce ATP-gatedcurrents with the properties seen in some sensory neurons (Lewis, et al.(1995) Nature 377:432-435).

P2X receptor subunits are found on afferents in rodent and human bladderurothelium. Data exists suggesting that ATP may be released fromepithelial/endothelial cells of the urinary bladder or other holloworgans as a result of distention (Burnstock (1999) J. Anatomy194:335-342; and Ferguson et al. (1997) J. Physiol. 505:503-511). ATPreleased in this manner may serve a role in conveying information tosensory neurons located in subepithelial components, e.g., suburotheliallamina propria (Namasivayam, et al. (1999) BJU Intl. 84:854-860). TheP2X receptors have been studied in a number of neurons, includingsensory, sympathetic, parasympathetic, mesenteric, and central neurons(Thong, et al. (1998) Br. J. Pharmacol. 125:771-781). These studiesindicate that purinergic receptors play a role in afferentneurotransmission from the bladder, and that modulators of P2X receptorsare potentially useful in the treatment of bladder disorders and othergenitourinary diseases or conditions.

Recent evidence also suggests a role of endogenous ATP and purinergicreceptors in nociceptive responses in mice (Tsuda, et al. (1999) Br. J.Pharmacol. 128:1497-1504). ATP-induced activation of P2X receptors ondorsal root ganglion nerve terminals in the spinal cord has been shownto stimulate release of glutamate, a key neurotransmitter involved innociceptive signaling (Gu and MacDermott, Nature 389:749-753 (1997)).P2X₃ receptors have been identified on nociceptive neurons in the toothpulp (Cook et al., Nature 387:505-508 (1997)). ATP released from damagedcells may thus lead to pain by activating P2X₃ and/or P2X_(2/3)containing receptors on nociceptive sensory nerve endings. This isconsistent with the induction of pain by intradermally applied ATP inthe human blister-base model (Bleehen, Br J Pharmacol 62:573-577(1978)). P2X antagonists have been shown to be analgesic in animalmodels (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol350:618-625 (1994)). This evidence suggests that P2X₂ and P2X₃ areinvolved in nociception, and that modulators of P2X receptors arepotentially useful as analgesics.

Other researchers have shown that P2X₃ receptors are expressed in humancolon, and are expressed at higher levels in inflamed colon than innormal colon (Y. Yiangou et al, Neurogastroenterol Mot (2001)13:365-69). Other researchers have implicated the P2X₃ receptor indetection of distension or intraluminal pressure in the intestine, andinitiation of reflex contractions (X. Bian et al., J Physiol (2003)551.1:309-22), and have linked this to colitis (G. Wynn et al., Am JPhysiol Gastrointest Liver Physiol (2004) 287:G647-57).

Inge Brouns et al. (Am J Respir Cell Mol Biol (2000) 23:52-61) foundthat P2X₃ receptors are expressed in pulmonary neuroepithelial bodies(NEBs), implicating the receptor in pain transmission in the lung. Morerecently, others have implicated P2X₂ and P2X₃ receptors in pO₂detection in pulmonary NEBs (W. Rong et al., J Neurosci (2003)23(36):11315-21).

There is accordingly a need for compounds that act as modulators of P2Xreceptors, including antagonists of P2X₃ and P2X_(2/3) receptors, aswell as a need for methods of treating diseases, conditions anddisorders mediated by P2X₃ and/or P2X_(2/3) receptors. The presentinvention satisfies these needs as well as others.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is optionally substituted tetrazolyl;

R² is optionally substituted phenyl, optionally substituted pyridinyl,optionally substituted pyrimidinyl, optionally substituted pyridazinylor optionally substituted thiophenyl;

R³ is:

-   -   hydrogen;    -   C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl; or    -   cyano;

R⁴ is:

-   -   hydrogen;    -   C₁₋₆alkyl; or    -   hetero-C₁₋₆alkyl;    -   or R³ and R⁴ together with the atom to which they are attached        may form a C₃₋₆ carbocyclic ring;

R⁵ is:

-   -   C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl;    -   halo-C₁₋₆alkyl;    -   N—C₁₋₆alkylamino;    -   N,N-di-(C₁₋₆alkyl)-amino;    -   C₃₋₇cycloalkyl;    -   aryl;    -   heteroaryl;    -   heterocyclyl;    -   C₃₋₇cycloalkyl-C₁₋₆alkyl;    -   heteroaryl-C₁₋₆alkyl;    -   heterocyclyl-C₁₋₆alkyl;    -   aryloxy-C₁₋₆alkyl;    -   —(CR^(a)R^(b))_(m)—C(O)—R⁸ wherein:        -   m is 0 or 1;        -   R^(a) and R^(b) each independently is:            -   hydrogen; or            -   C₁₋₆alkyl; and        -   R⁸ is:            -   hydrogen;            -   C₁₋₆alkyl;            -   hetero-C₁₋₆alkyl;            -   C₃₋₇cycloalkyl;            -   aryl;            -   heteroaryl;            -   heterocyclyl;            -   C₃₋₇cycloalkyl-C₁₋₆alkyl;            -   aryl-C₁₋₆alkyl;            -   heteroaryl-C₁₋₆alkyl;            -   heterocyclyl-C₁₋₆alkyl;            -   C₃₋₇cycloalkyloxy;            -   aryloxy;            -   heteroaryloxy;            -   heterocyclyloxy;            -   C₃₋₇cycloalkyloxy-C₁₋₆alkyl;            -   aryloxy-C₁₋₆alkyl;            -   heteroaryloxy-C₁₋₆alkyl;            -   heterocyclyloxy-C₁₋₆alkyl; or            -   —NR⁹R¹⁰, wherein:                -   R⁹ is:                -    hydrogen; or                -    C₁₋₆alkyl; and                -   R¹⁰ is:                -    hydrogen;                -    C₁₋₆alkyl;                -    hetero-C₁₋₆alkyl;                -    C₃₋₇cycloalkyl;                -    aryl;                -    heteroaryl;                -    heterocyclyl;                -    C₃₋₇cycloalkyl-C₁₋₆alkyl;                -    aryl-C₁₋₆alkyl;                -    heteroaryl-C₁₋₆alkyl; or                -    heterocyclyl-C₁₋₆alkyl; and

or R⁴ and R⁵ together with the atom to which they are attached may forma C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy;

or R⁴ and R⁵ together with the atom to which they are attached may forma C₄₋₆ heterocyclic ring containing one or two heteroatoms eachindependently selected from O, N and S;

or R³, R⁴ and R⁵ together with the atom to which they are attached mayform a six-membered heteroaryl containing one or two nitrogen atoms, andwhich is optionally substituted with halo, amino or C₁₋₆alkyl;

R⁶ is:

-   -   C₁₋₆alkyl;    -   C₁₋₆alkyloxy;    -   halo;    -   C₁₋₆haloalkyl; or    -   cyano;

provided that when R¹ is tetrazol-1-yl, R² is 4-methyl-phenyl, R³ ismethyl, R⁴ is hydrogen and R⁶ is hydrogen, then R⁵ is not furan-2-yl.

The invention also provides and pharmaceutical compositions comprisingthe compounds, methods of using the compounds, and methods of preparingthe compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean amoiety of the formula —OR, wherein R is an alkyl moiety as definedherein. Examples of alkoxy moieties include, but are not limited to,methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —R′—R″, where R′ is oxoand R″ is alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —R′—R″, where R′ is —SO₂—and R″ is alkyl as defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—R″—R′″ where R′ isalkylene, R″ is —SO₂— and R′″ is alkyl as defined herein.

“Alkylamino means a moiety of the formula —NR—R′ wherein R is hydrogenor alkyl and R′ is alkyl as defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R¹ is amino and R is alkyleneas defined herein.

“Aminoalkyl” includes aminomethyl, aminoethyl, 1-aminopropyl,2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may besubstituted once or twice with alkyl to provide “alkylaminoalkyl” and“dialkylaminoalkyl” respectively. “Alkylaminoalkyl” includesmethylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyland the like. “Dialkylaminoalkyl” includes dimethylaminomethyl,dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, andthe like.

“Aminoalkoxy” means a group —OR—R′ wherein R¹ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, optionally substituted phenyl,naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl,oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl,benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl,benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl,benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and thelike, including partially hydrogenated derivatives thereof.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Cyanoalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(e) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl,heteroaryl, cyclohexyl or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,heteroalkyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl),—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b)(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R^(a) and R^(b) are, independently of each other,hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).Certain preferred optional substituents for “aryl”, phenyl”,“heteroaryl” “cycloalkyl” or “heterocyclyl” include alkyl, halo,haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. More preferredsubstituents are methyl, fluoro, chloro, trifluoromethyl, methoxy, aminoand methanesulfonyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

-   -   acid addition salts formed with inorganic acids such as        hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,        phosphoric acid, and the like; or formed with organic acids such        as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic        acid, citric acid, ethanesulfonic acid, fumaric acid,        glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,        hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid,        maleic acid, malic acid, malonic acid, mandelic acid,        methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid,        propionic acid, salicylic acid, succinic acid, tartaric acid,        p-toluenesulfonic acid, trimethylacetic acid, and the like; or    -   salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic or inorganic base. Acceptable        organic bases include diethanolamine, ethanolamine,        N-methylglucamine, triethanolamine, tromethamine, and the like.        Acceptable inorganic bases include aluminum hydroxide, calcium        hydroxide, potassium hydroxide, sodium carbonate and sodium        hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Disorders of the urinary tract” or “uropathy” used interchangeably with“symptoms of the urinary tract” means the pathologic changes in theurinary tract. Examples of urinary tract disorders include, but are notlimited to, incontinence, benign prostatic hypertrophy (BPH),prostatitis, detrusor hyperreflexia, outlet obstruction, urinaryfrequency, nocturia, urinary urgency, overactive bladder, pelvichypersensitivity, urge incontinence, urethritis, prostatodynia,cystitis, idiophatic bladder hypersensitivity, and the like.

“Disease states associated with the urinary tract” or “urinary tractdisease states” or “uropathy” used interchangeably with “symptoms of theurinary tract” mean the pathologic changes in the urinary tract, ordysfunction of urinary bladder smooth muscle or its innervation causingdisordered urinary storage or voiding. Symptoms of the urinary tractinclude, but are not limited to, overactive bladder (also known asdetrusor hyperactivity), outlet obstruction, outlet insufficiency, andpelvic hypersensitivity.

“Overactive bladder” or “detrusor hyperactivity” includes, but is notlimited to, the changes symptomatically manifested as urgency,frequency, altered bladder capacity, incontinence, micturitionthreshold, unstable bladder contractions, sphincteric spasticity,detrusor hyperreflexia (neurogenic bladder), detrusor instability, andthe like.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy (BPH), urethral stricture disease, tumors, low flow rates,difficulty in initiating urination, urgency, suprapubic pain, and thelike.

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, mixed incontinence,stress incontinence, and the like.

“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain,interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadynia,urethritis, orchidalgia, overactive bladder, and the like.

“Respiratory disorder” refers to, without limitation, chronicobstructive pulmonary disease (COPD), asthma, bronchospasm, and thelike.

“Gastrointestinal disorder” (“GI disorder”) refers to, withoutlimitation, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease(IBD), biliary colic and other biliary disorders, renal colic,diarrhea-dominant IBS, pain associated with GI distension, and the like.

“Pain” includes, without limitation, inflammatory pain; surgical pain;visceral pain; dental pain; premenstrual pain; central pain; pain due toburns; migraine or cluster headaches; nerve injury; neuritis;neuralgias; poisoning; ischemic injury; interstitial cystitis; cancerpain; viral, parasitic or bacterial infection; post-traumatic injury; orpain associated with irritable bowel syndrome.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen or nitrogen atom in the structures herein indicatesthe presence of a hydrogen atom. Where a chiral center exists in astructure but no specific stereochemistry is shown for the chiralcenter, both enantiomers associated with the chiral structure areencompassed by the structure.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is optionally substituted tetrazolyl;

R² is optionally substituted phenyl, optionally substituted pyridinyl,optionally substituted pyrimidinyl, optionally substituted pyridazinylor optionally substituted thiophenyl;

R³ is:

-   -   hydrogen;    -   C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl; or    -   cyano;

R⁴ is:

-   -   hydrogen;    -   C₁₋₆alkyl; or    -   hetero-C₁₋₆alkyl;

or R³ and R⁴ together with the atom to which they are attached may forma C₃₋₆ carbocyclic ring;

R⁵ is:

-   -   C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl;    -   halo-C₁₋₆alkyl;    -   N—C₁₋₆alkylamino;    -   N,N-di-(C₁₋₆alkyl)-amino;    -   C₃₋₇cycloalkyl;    -   aryl;    -   heteroaryl;    -   heterocyclyl;    -   C₃₋₇cycloalkyl-C₁₋₆alkyl;    -   heteroaryl-C₁₋₆alkyl;    -   heterocyclyl-C₁₋₆alkyl;    -   aryloxy-C₁₋₆alkyl;    -   —(CR^(a)R^(b))_(m)—C(O)—R⁸ wherein:        -   m is 0 or 1;        -   R^(a) and R^(b) each independently is:            -   hydrogen; or            -   C₁₋₆alkyl; and        -   R⁸ is:            -   hydrogen;            -   C₁₋₆alkyl;            -   hetero-C₁₋₆alkyl;            -   C₃₋₇cycloalkyl;            -   aryl;            -   heteroaryl;            -   heterocyclyl;            -   C₃₋₇cycloalkyl-C₁₋₆alkyl;            -   aryl-C₁₋₆alkyl;            -   heteroaryl-C₁₋₆alkyl;            -   heterocyclyl-C₁₋₆alkyl;            -   C₃₋₇cycloalkyloxy;            -   aryloxy;            -   heteroaryloxy;            -   heterocyclyloxy;            -   C₃₋₇cycloalkyloxy-C₁₋₆alkyl;            -   aryloxy-C₁₋₆alkyl;            -   heteroaryloxy-C₁₋₆alkyl;            -   heterocyclyloxy-C₁₋₆alkyl; or            -   —NR⁹R¹⁰, wherein:                -   R⁹ is:                -    hydrogen; or                -    C₁₋₆alkyl; and                -   R¹⁰ is:                -    hydrogen;                -    C₁₋₆ alkyl;                -    hetero-C₁₋₆alkyl;                -    C₃₋₇cycloalkyl;                -    aryl;                -    heteroaryl;                -   heterocyclyl;                -    C₃₋₇cycloalkyl-C₁₋₆alkyl;                -    aryl-C₁₋₆alkyl;                -    heteroaryl-C₁₋₆alkyl; or                -    heterocyclyl-C₁₋₆alkyl; and

or R⁴ and R⁵ together with the atom to which they are attached may forma C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy;

or R⁴ and R⁵ together with the atom to which they are attached may forma C₄₋₆ heterocyclic ring containing one or two heteroatoms eachindependently selected from O, N and S;

or R³, R⁴ and R⁵ together with the atom to which they are attached mayform a six-membered heteroaryl containing one or two nitrogen atoms, andwhich is optionally substituted with halo, amino or C₁₋₆alkyl;

R⁶ is:

-   -   C₁₋₆alkyl;    -   C₁₋₆alkyloxy;    -   halo;    -   C₁₋₆haloalkyl; or    -   cyano;

provided that when R¹ is tetrazol-1-yl, R² is 4-methyl-phenyl, R³ ismethyl, R⁴ is hydrogen and R⁶ is hydrogen, then R⁵ is not furan-2-yl.

In many embodiments of formula I, R² is optionally substituted phenyl,such as phenyl optionally substituted once, twice or three times,preferably once or twice, with any of C₁₋₆alkyl, C₁₋₆alkyloxy, halo,C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano.

In certain embodiments R² is phenyl substituted once or twice with haloor methyl.

In many embodiments of formula I, R² is phenyl substituted at the4-position with methyl or halo and optionally substituted at the 2- and6-positions with halo.

In many embodiments of formula I, R² is phenyl substituted at the4-position with methyl or halo and optionally substituted at the2-position with halo.

In certain embodiments of formula I, R² is 4-methyl-phenyl,2-fluoro-4-methyl-phenyl, 2-chloro-4-fluoro-phenyl,4-chloro-2-fluoro-phenyl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, or2-chloro-4-methyl-phenyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl or4-chloro-phenyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl.

In certain embodiments of formula I, R² is 2-fluoro-4-methyl-phenyl.

In certain embodiments of formula I, R² is 2-chloro-4-fluoro-phenyl.

In certain embodiments of formula I, R² is 4-chloro-2-fluoro-phenyl.

In certain embodiments of formula I, R² is 2,4-dichloro-phenyl.

In certain embodiments of formula I, R² is 2,4-difluoro-phenyl.

In certain embodiments of formula I, R² is 2-chloro-4-methyl-phenyl.

In many embodiments of formula I, R² is optionally substitutedpyridinyl. Exemplary pyridinyl include pyridin-2-yl, andpyridin-2-one-1-yl, each optionally substituted once, twice or threetimes, preferably once or twice, with any of C₁₋₆alkyl, C₁₋₆alkyloxy,halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano.Preferred pyridyl include 4-methyl-pyridin-2-yl, 4-fluoro-pyridin-2-yland 4-methyl-pyridin-2-one-1-yl.

In certain embodiments of formula I, R² is pyridin 2-yl substituted withmethyl or halo at the 5-position.

In certain embodiments of formula I, R² is pyridin 2-yl substituted withmethyl or halo at the 5-position and optionally substituted with halo atthe 3-position.

In certain embodiments of formula I, R² is 5-methyl-pyridin-2-yl,5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl,5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl or 3,5-dichloro-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-methyl-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-chloro-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-fluoro-pyridin-2-yl.

In certain embodiments of formula I, R² is5-methyl-3-fluoro-pyridin-2-yl.

In certain embodiments of formula I, R² is5-methyl-3-chloro-pyridin-2-yl.

In certain embodiments of formula I, R² is 3,5-difluoro-pyridin-2-yl.

In certain embodiments of formula I, R² is 3,5-dichloro-pyridin-2-yl.

In certain embodiments of formula I, R² is optionally substitutedpyridazinyl. In such embodiments R² may be 6-chloro-pyridazinyl or6-methyl-pyridazinyl, preferably 6-chloro-pyridazinyl.

In certain embodiments of formula I, R² is optionally substitutedthiophenyl. In such embodiments R² may be thiophen-2-yl optionallysubstituted with C₁₋₆alkyl or halo. Preferred thiophenyl include3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl and5-chloro-thiophen-2-yl.

In many embodiments of formula I, R⁶ is hydrogen. In certain embodimentsof formula I, R⁶ may be methyl.

In many embodiments of formula I, R³ is hydrogen.

In many embodiments of formula I, R³ is C₁₋₆alkyl. A preferred C₁₋₆alkylin such embodiments is methyl.

In many embodiments of formula I, R⁴ is C₁₋₆alkyl. A preferred C₁₋₆alkylin such embodiments is methyl.

In many embodiments of formula I, R³ is hydrogen and R⁴ is C₁₋₆alkyl,preferably methyl.

In certain embodiments of formula I, R³ and R⁴ are hydrogen.

In certain embodiments of formula I, R³ and R⁴ together with the atom towhich they are attached may form a C₃₋₆ carbocyclic ring.

In certain embodiments of formula I, R³ and R⁴ together with the atom towhich they are attached may form a cyclopropyl group.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom towhich they are attached form a C₃₋₆ carbocyclic ring that is optionallysubstituted with hydroxy.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom towhich they are attached form a cyclopropyl.

In certain embodiments of formula I, R³ is hydrogen and R⁴ and R⁵together with the atom to which they are attached form a cyclopropyl.

In certain embodiments of formula I, R³ is hydrogen and R⁴ and R⁵together with the atom to which they are attached form a cyclopentyloptionally substituted with hydroxy.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom towhich they are attached form a C₄₋₆ heterocyclic ring containing one ortwo heteroatoms each independently selected from O, N and S.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom towhich they are attached form a piperidinyl group or oxetanyl ring group.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom towhich they are attached form a piperidin-3-yl group or an oxetan-3-ylgroup.

In certain embodiments of formula I, R³, R⁴ and R⁵ together with theatom to which they are attached form a six-membered heteroarylcontaining one or two nitrogen atoms, and which is optionallysubstituted with halo, amino or C₁₋₆alkyl.

In certain embodiments of formula I, R³, R⁴ and R⁵ together with theatom to which they are attached form a heteroaryl selected from2-oxo-1,2-dihydro-pyrimidinyl, pyridinyl, pyrimidinyl, pyridazinyl orpyridazinyl, each optionally substituted with methyl or amino.

In certain embodiments of formula I, R³, R⁴ and R⁵ together with theatom to which they are attached form a heteroaryl selected from2-oxo-1,2-dihydro-pyrimidin-4-yl, 2-oxo-1,2-dihydro-pyrimidin-4-yl,1-methyl-2-oxo-1,2-dihydro-pyrimidin-4-yl, 6-methyl-pyridin-3-yl,pyridazin-4-yl, 6-amino-pyridin-2-yl, 2-aminopyrimidin-4-yl or2-amino-pyrimidin-3-yl.

In many embodiments of formula I, R¹ is tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrazol-5-yl optionallysubstituted at the 1-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,hetero-C₁₋₆alkyl, C₃₋₆-cycloalkyl, C₃₋₆cycloalkyl-C₁₋₆alkyl or cyano.Preferably in such embodiments the 1-position is substituted withC₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,hetero-C₁₋₆alkyl, C₃₋₆-cycloalkyl, C₃₋₆cycloalkyl-C₁₋₆alkyl or cyano.

In certain embodiments of formula I, R¹ is tetrazol-1-yl substituted atthe 5-position with C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrazol-1-yl substituted atthe 5-position with halo-C₁₋₄alkyl.

In certain embodiments of formula I, R¹ is tetrazol-1-yl substituted atthe 5-position with hetero-C₁₋₆alkyl selected from hydroxy-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, orN,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrazol-1-yl substituted atthe 5-position with halo-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrazol-1-yl optionallysubstituted at the 5-position with methyl, ethyl, n-propyl, n-butyl,isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclopropylmethyl,trifluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 1-methoxy-ethyl,1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, ordimethylaminomethyl.

In certain embodiments of formula I, R¹ is tetrazol-1-yl substituted atthe 5-position with methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, cyclopropyl or cyclopropylmethyl.

In certain embodiments of formula I, R⁵ is: C₁₋₆alkyl;C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl;N—C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl;C₃₋₇cycloalkyl; optionally substituted phenyl; heteroaryl, orheterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁵ is N—C₁₋₆alkyl-amino-C₁₋₆alkylsubstituted with halo.

In certain embodiments of formula I, R⁵ is: C₁₋₆alkyloxy-C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁵ is C₁₋₆alkyloxy-C₁₋₆alkyl. Onepreferred C₁₋₆alkyloxy-C₁₋₆alkyl is methoxymethyl.

In certain embodiments of formula I, R⁵ is hydroxy-C₁₋₆alkyl. Onepreferred hydroxy-C₁₋₆alkyl is hydroxymethyl.

In certain embodiments of formula I, R⁵ is heteroaryl.

In certain embodiments where R⁵ is heteroaryl, such heteroaryl may bepyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl,3-oxo-2,3-dihydro-isoxazolyl, tetrazolyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and benzimidazolyl,each of which may be optionally substituted one, two or three times witha group or groups independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆halo-C₁₋₆alkyl, halo, amino, N—C₁₋₆alkyl-amino, orN,N-di-(C₁₋₆alkyl)-amino. More preferably, such heteroaryl may beoptionally substituted once or twice with a group or groupsindependently selected from methyl, ethyl, n-propyl, fluoro, chloro,trifluoromethyl, amino, methylamino or dimethylamino.

In certain embodiments where R⁵ is heteroaryl, such heteroaryl may bepyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or thiazolyl,each of which may be optionally substituted once or twice with a groupor groups independently selected from methyl, ethyl, n-propyl, fluoro,chloro, amino, methylamino or dimethylamino.

In certain embodiments where R⁵ is heteroaryl, such heteroaryl may bepyridinyl, pyrimidinyl, or pyrazinyl, each of which may be optionallysubstituted once or twice with a group or groups independently selectedfrom methyl, fluoro, chloro, amino, methylamino or dimethylamino.

In certain embodiments of formula I, where R⁵ is heteroaryl, suchheteroaryl may be thiophen-2-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, oxazol-2-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl,5-methyl-pyrazin-2-yl, imidazol-1-yl, pyrazol-1-yl,3,5-dimethyl-pyrazol-1-yl, 2-methyl-thiazol-4-yl,3-(2-chloro-phenyl)[1,2,4]-oxadiazol-5-yl,3-(pyridin-4-yl)-[1,2,4]-oxadiazol-5-yl, pyridazin-3-yl,2-methyl-pyrazol-3-yl, thiazol-5-yl, 1-methyl-imidazol-2-yl,6-chloro-pyrimidin-4-yl, 4-ethyl[1,2,4]-triazol-3-yl,1,3,5-trimethyl-pyrazol-4-yl, 1,5-dimethyl-pyrazol-4-yl,1,3-dimethyl-pyrazol-4-yl, 3-(2-methoxy-ethyl)-[1,2,4]-oxadiazol-5-yl,3-(pyridin-3-yl-[1,2,4]-oxadiazol-5-yl, tetrazol-5-yl, pyrazol-3-yl,4-amino-2-methyl-pyrimidin-5-yl, 2-amino-pyrimidin-4-yl,6-methoxy-pyridazin-3-yl, 3-oxo-2,3-dihydro-isoxazol-5-yl,3-methyl-thiophen-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl,4-methyl-isoxazol-3-yl, 3-trifluoromethyl-pyrazol-1-yl,1-methyl-pyrazol-3-yl, 3-methyl-pyrazol-1-yl,5-methyl-3-trifluoromethyl-pyrazol-1-yl,5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl,imidazo[2,1-b]-thiazol-6-yl, thiazol-4-yl, 2-propyl-pyrazol-3-yl,2-ethyl-pyrazol-3-yl, 5-amino-pyridazin-2-yl, 3-amino-pyridazin-2-yl,3-chloro-pyridazin-2-yl, 2-amino-pyrimidin-5-yl, 1-methyl-imidazol-4-yl,6-amino-pyridin-3-yl, 6-amino-pyridazin-2-yl, 2-amino-pyridin-4-yl,2-dimethylamino-pyrimidin-5-yl, 6-amino-pyridin-2-yl,2-methylamino-pyridin-4-yl, 2-dimethylamino-pyridin4-yl,3-methyl-2-dimethylamino-pyridin-4-yl, pyrimidin-5-yl,2-methyl-pyridin-4-yl, 6-methylamino-pyridin-3-yl,6-dimethylamino-pyridin-3-yl, 6-methylamino-pyrimidin-4-yl,6-dimethylamino-pyridin-3-yl, 6-methylamino-pyridin-3-yl,2-methylamino-pyrimidin-5-yl, 6-methyl-pyridin-3-yl,4-methyl-thiazol-2-yl, 2,6-dimethyl-pyridin-3-yl,imidazo[1,2-a]pyridin-2-yl, 6-methyl-pyridin-2-yl, 1-ethyl-pyrazol-3-yl,3-methyl-pyridin-2-yl, 4-methyl-thiazol-5-yl, 1-ethyl-imidazol-2-yl,1-methyl-pyrazol-4-yl, imidazo[4,5-b]pyridin-2-yl,3,5-difluoro-pyridin-2-yl, 6-fluoro-pyridin-2-yl,1,5-dimethyl-pyrazol-3-yl, 5-methyl-pyridin-2-yl,6-trifluoromethyl-pyridin-3-yl, 5-methyl-isoxazol-3-yl,5-methyl-imidazol-2-yl, 5-methoxy-benzimidazol-2-yl,[1,2,4]triazol-3-yl, and 8-methyl-imidazo[1,2-a]pyridin-2-yl.

In certain embodiments of formula I, R⁵ is heterocyclyl-C₁₋₆alkyl.

In embodiments where R⁵ is heterocyclyl-C₁₋₆alkyl, suchheterocyclyl-C₁₋₆alkyl may be heterocyclyl-methyl such asmorpholinomethyl, piperidinyl-methyl, piperazinyl-methyl,thiomorpholinylmethyl, pyrrolidinylmethyl, or azetidinylmethyl, theheterocyclyl portion of each of which may be optionally substituted onceor twice with a group or groups independently selected from methyl,methoxy, halo, methanesulfonyl, oxo or acetyl.

In embodiments where R⁵ is heterocyclyl-methyl, such heterocyclylmethylmay be morpholin-4-yl-methyl, 4-methanesulfonyl-piperazin-1-yl-methyl,4-acetyl-piperazin-1-yl-methyl, piperidin-1-yl,thiomorpholin-4-yl-methyl, 4-methyl-piperazin-1-yl-methyl,3-oxo-piperazin-1-yl-methyl, 3-methoxy-piperidin-1-yl-methyl,4-methoxy-piperidin-1-yl-methyl, 4-hydroxy-piperidin-1-yl-methyl,1-oxo-thiomorpholin-4-yl-methyl, 3-hydroxy-pyrrolidin-1-yl-methyl,azetidin-3-yl-methyl, 4-methanesulfonyl-piperidin-1-yl-methyl,4-fluoro-piperidin1-yl-methyl, 4-acetyl-3-methyl-piperazin-1-yl-methyl,4-acetyl-3,5-dimethyl-piperazin-1-yl-methyl,2,6-dimethyl-morpholin-4-yl-methyl, 4,4-difluoro-piperidin1-yl-methyl,3-fluoro-piperidin1-yl-methyl, 4-methyl-4-hydroxy-piperidin1-yl-methyl,or 3-fluoro-4-methoxy-piperidin1-yl-methyl.

In certain embodiments of formula I, R⁵ is hydroxymethyl, methoxymethyl,pyrazin-2-yl or 5-methyl-pyrazin-2-yl.

In certain embodiments of formula I, R⁵ is hydroxymethyl.

In certain embodiments of formula I, R⁵ is methoxymethyl.

In certain embodiments of formula I, R⁵ is pyrazin-2-yl.

In certain embodiments of formula I, R⁵ is 5-methyl-pyrazin-2-yl.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C_(1/6)alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl,C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl;2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl;2,4-difluoro-phenyl; or 2-chloro-4-methyl-phenyl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;amino-C₁₋₆alkyl; N—C₁₋₆alkyl-amino-C₁₋₆alkyl;N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl; C₃₋₇cycloalkyl; optionally substitutedphenyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl,5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or3,5-dichloro-pyridin-2-yl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkylsulfanyl-C₁₋₆alkyl; 6alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl;N—C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl;C₃₋₇cycloalkyl; optionally substituted phenyl; heteroaryl, orheterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₃₋₆-cycloalkyl, orC₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl;2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl;2,4-difluoro-phenyl; or 2-chloro-4-methyl-phenyl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl;piperidin-1-yl methyl optionally substituted at the 4-position withmethyl, methanesulfonyl or acetyl; 1,1,-dioxo-thiomorpholin-1-yl;piperidin-1-yl-methyl optionally substituted once or twice with a groupor groups selected independently from methyl, methoxy or halo;pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl;wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyland thiazolyl each may be optionally substituted once or twice with agroup or groups selected independently from methyl, methylamino,dimethylamino and halo.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl,5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or3,5-dichloro-pyridin-2-yl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl;piperidin-1-yl methyl optionally substituted at the 4-position withmethyl, methanesulfonyl or acetyl; 1,1,-dioxo-thiomorpholin-1-yl;piperidin-1-yl optionally substituted once or twice with a group orgroups selected independently from methyl, methoxy or halo; pyridinyl;pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; whereinthe pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl andthiazolyl each may be optionally substituted once or twice with a groupor groups selected independently from methyl, methylamino, dimethylaminoand halo.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl;2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl;2,4-difluoro-phenyl; or 2-chloro-4-methyl-phenyl;

R³ is hydrogen; and

R⁴ and R⁵ together form a cyclopropyl group.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl,5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or3,5-dichloro-pyridin-2-yl; R³ is hydrogen; and

R⁴ and R⁵ together form a cyclopropyl group.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆ alkyl, hydroxy-C₁₋₆alkyl,N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, orC₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl;2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl;2,4-difluoro-phenyl; or 2-chloro-4-methyl-phenyl;

R³ is hydrogen;

R⁴ is methyl; and

R⁵ is methoxymethyl, hydroxymethyl, or pyridazin-2-yl.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl,C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl,5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or3,5-dichloro-pyridin-2-yl;

R³ is hydrogen;

R⁴ is methyl; and

R⁵ is methoxymethyl, hydroxymethyl, or pyridazin-2-yl.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl,C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl;2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl;2,4-difluoro-phenyl; or 2-chloro-4-methyl-phenyl; R³ and R⁴ arehydrogen; and

R⁵ is 5-methyl-pyridazin-2-yl.

In certain embodiments of formula I:

R¹ is tetrazol-1-yl optionally substituted at the 5-position withC₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl,C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl,5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or3,5-dichloro-pyridin-2-yl;

R³ and R⁴ are hydrogen; and

R⁵ is 5-methyl-pyridazin-2-yl.

In certain embodiments of the invention where R² is optionallysubstituted phenyl, R³ is hydrogen and R⁴ is methyl, the subjectcompounds may be represented by formula IIa or formula

or a pharmaceutically acceptable salt thereof,wherein:

R¹¹ and R¹² each independently is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano;

R¹³ is hydrogen, C₁₋₆alkyl, halo-C₁₋₆alkyl, hetero-C₁₋₆alkyl,C₃₋₆-cycloalkyl or C₃₋₆cycloalkyl-C₁₋₆alkyl. or cyano; and

R⁵ is as defined herein.

In certain embodiments of the invention where R² is optionallysubstituted phenyl, and R³ and R⁴ are hydrogen, the subject compoundsmay be represented by formula IIc:

or a pharmaceutically acceptable salt thereof, wherein R⁵, R¹¹, R¹² andR¹³ are as defined herein.

In certain embodiments of the invention the subject compounds are offormula Ma or Mb:

or a pharmaceutically acceptable salt thereof, wherein R⁵, R¹² and R¹³are as defined herein;

In certain embodiments of the invention the subject compounds are offormula IIIc:

or a pharmaceutically acceptable salt thereof, wherein R⁵, R¹² and R¹³are as defined herein;

In certain embodiments of the invention where R² is optionallysubstituted pyridinyl, R³ is hydrogen and R⁴ is methyl, the subjectcompounds may be represented by formula IVa or formula IVb:

or a pharmaceutically acceptable salt thereof, wherein R⁵, R¹¹, R¹² andR¹³ are as defined herein.

In certain embodiments of the invention where R² is optionallysubstituted pyridinyl, and R³ and R⁴ are hydrogen, the subject compoundsmay be represented by formula IVc:

or a pharmaceutically acceptable salt thereof, wherein R⁵, R¹¹, R¹² andR¹³ are as defined herein.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb, IVc, R¹¹ is halo or methyl, and R¹² is hydrogen, halo ormethyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is:

C₁₋₆alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl and isopentyl;

hetero-C₁₋₆alkyl selected from C₁₋₆alkyloxy-C₁₋₆alkyl,hydroxy-C₁₋₆alkyl, C₁₋₆alkylsulfanyl-C₁₋₆alkyl,C₁₋₆alkyl-sulfinyl-C₁₋₆alkyl, C₁₋₆alkyl-sulfonyl-C₁₋₆alkyl,amino-C₁₋₆alkyl, N—C₁₋₆alkylamino-C₁₋₆alkyl, andN,N-di-C₁₋₆alkylamino-C₁₋₆alkyl, the alkyl portions of which may beoptionally substituted with halo;

C₃₋₇cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, each optionally substituted;

aryl selected from optionally substituted phenyl and optionallysubstituted naphthyl; heteroaryl selected from pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, oxadiazolyl,3-oxo-2,3-dihydro-isoxazolyl, tetrazolyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, benzimidazolyl,isoxazolyl and isothiazolyl, each optionally substituted;

heterocyclyl selected from piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,pyranyl, pyrrolidinyl, tetrahydrofuranyl,2-oxa-8-aza-spiro[4.5]decan-8-yl, 2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl,and 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl, and azetidinyl, eachoptionally substituted;

C₃₋₇cycloalkyl-C₁₋₆alkyl selected from cyclopropyl-C₁₋₆alkyl,cyclobutyl-C₁₋₆alkyl, cyclopentyl-C₁₋₆alkyl and cyclohexyl-C₁₋₆alkyl,the cycloalkyl portion of each being optionally substituted;

heteroaryl-C₁₋₆alkyl selected from pyridinyl-C₁₋₆alkyl,pyrimidinyl-C₁₋₆alkyl, pyridazinyl-C₁₋₆alkyl, pyrazinyl-C₁₋₆alkyl,furanyl-C₁₋₆alkyl, pyrrolyl-C₁₋₆alkyl, oxazolyl-C₁₋₆alkyl,thiazolyl-C₁₋₆alkyl, imidazolyl-C₁₋₆alkyl, pyrazolyl-C₁₋₆alkyl,triazolyl-C₁₋₆alkyl, oxadiazolyl-C₁₋₆alkyl,3-oxo-2,3-dihydro-isoxazolyl-C₁₋₆alkyl,imidazo[2,1-b]thiazolyl-C₁₋₆alkyl, imidazo[1,2-a]pyridinyl-C₁₋₆alkyl,imidazo[4,5-b]pyridinyl-C₁₋₆alkyl, benzimidazolyl-C₁₋₆alkyl,isoxazolyl-C₁₋₆alkyl and isothiazolyl-C₁₋₆alkyl, the heteroaryl portionof each being optionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperidinyl-C₁₋₆alkyl,piperazinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl, thiomorpholinyl-C₁₋₆alkyl,1-oxo-thiomorpholinyl-C₁₋₆alkyl, 1,1-dioxo-thiomorpholinyl-C₁₋₆alkyl,pyranyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl, tetrahydrofuranyl-C₁₋₆alkyl,2-oxa-8-aza-spiro[4.5]decan-8-yl-C₁₋₆alkyl,2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl-C₁₋₆alkyl,3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl-C₁₋₆alkyl, and azetidin-C₁₋₆alkyl,the heterocyclyl portion of each being optionally substituted;

aryloxy-C₁₋₆alkyl selected from phenoxy-C₁₋₆alkyl andnaphthyloxy-C₁₋₆alkyl, the aryl portion of each being optionallysubstituted; or

—C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is as defined herein.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is:

C₁₋₆alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl and isopentyl;

hetero-C₁₋₆alkyl selected from C₁₋₆alkyloxy-C₁₋₆alkyl,hydroxy-C₁₋₆alkyl, C₁₋₆alkylsulfanyl-C₁₋₆alkyl,C₁₋₆alkyl-sulfinyl-C₁₋₆alkyl, C₁₋₆alkyl-sulfonyl-C₁₋₆alkyl,amino-C₁₋₆alkyl, N—C₁₋₆alkylamino-C₁₋₆alkyl, andN,N-di-C₁₋₆alkylamino-C₁₋₆alkyl, the alkyl portions of which may beoptionally substituted with halo;

C₃₋₇cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, each optionally substituted;

aryl selected from optionally substituted phenyl and optionallysubstituted naphthyl; heteroaryl selected from pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, oxadiazolyl,3-oxo-2,3-dihydro-isoxazolyl, tetrazolyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, benzimidazolyl,isoxazolyl and isothiazolyl, each optionally substituted;

heterocyclyl selected from piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,pyranyl, pyrrolidinyl tetrahydrofuranyl and azetidinyl, each optionallysubstituted;

C₃₋₇cycloalkyl-C₁₋₆alkyl selected from cyclopropyl-C₁₋₆alkyl,cyclobutyl-C₁₋₆alkyl, cyclopentyl-C₁₋₆alkyl and cyclohexyl-C₁₋₆alkyl,the cycloalkyl portion of each being optionally substituted;

heteroaryl-C₁₋₆alkyl selected from pyridinyl-C₁₋₆alkyl,pyrimidinyl-C₁₋₆alkyl, pyridazinyl-C₁₆alkyl, pyrazinyl-C₁₋₆alkyl,furanyl-C₁₋₆alkyl, thienyl-C₁₋₆alkyl, pyrrolyl-C₁₋₆alkyl,oxazolyl-C₁₋₆alkyl, thiazolyl-C₁₋₆alkyl, imidazolyl-C₁₋₆alkyl,isoxazolyl-C₁₋₆alkyl and isothiazolyl-C₁₋₆alkyl, the heteroaryl portionof each being optionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperidinyl-C₁₋₆alkyl,piperazinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl, thiomorpholinyl-C₁₋₆alkyl,1-oxo-thiomorpholinyl-C₁₋₆alkyl, 1,1-dioxo-thiomorpholinyl-C₁₋₆alkyl,pyranyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl tetrahydrofuranyl-C₁₋₆alkyl,and azetidin-C₁₋₆alkyl, the heterocyclyl portion of each beingoptionally substituted;

aryloxy-C₁₋₆alkyl selected from phenoxy-C₁₋₆alkyl andnaphthyloxy-C₁₋₆alkyl, the aryl portion of each being optionallysubstituted; or

—C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is as defined herein.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₁₋₆alkyl selected from methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl andisopentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is hetero-C₁₋₆alkyl selected fromC₁₋₆alkyloxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylsulfanyl-C₁₋₆alkyl,amino-C₁₋₆alkyl, N—C₁₋₆alkylamino-C₁₋₆alkyl, andN,N-di-C₁₋₆alkylamino-C₁₋₆alkyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₃₋₇cycloalkyl selected from cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is aryl selected from optionally substitutedphenyl and optionally substituted naphthyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heteroaryl selected from pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, isoxazolyl and isothiazolyl, each optionallysubstituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heterocyclyl selected from piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, pyranyl, pyrrolidinyl and tetrahydrofuranyl,each optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₃₋₇cycloalkyl-C₁₋₆alkyl selected fromcyclopropyl-C₁₋₆alkyl, cyclobutyl-C₁₋₆alkyl, cyclopentyl-C₁₋₆alkyl andcyclohexyl-C₁₋₆alkyl, the cycloalkyl portion of each being optionallysubstituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heteroaryl-C₁₋₆alkyl selected frompyridinyl-C₁₋₆alkyl, pyrimidinyl-C₁₋₆alkyl, pyridazinyl-C₁₋₆alkyl,pyrazinyl-C₁₋₆alkyl, furanyl-C₁₆alkyl, thienyl-C₁₋₆alkyl,pyrrolyl-C₁₋₆alkyl, oxazolyl-C₁₋₆alkyl, thiazolyl-C₁₋₆alkyl,isoxazolyl-C₁₋₆alkyl and isothiazolyl-C₁₋₆alkyl, the heteroaryl portionof each being optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heterocyclyl-C₁₋₆alkyl selected frompiperidinyl-C₁₋₆alkyl, thiomorpholinyl-C₁₋₆alkyl,1-oxo-thiomorpholinyl-C₁₋₆alkyl, 1,1-dioxo-thiomorpholinyl-C₁₋₆alkyl,pyranyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl andtetrahydrofuranyl-C₁₋₆alkyl, the heterocyclyl portion of each beingoptionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is aryloxy-C₁₋₆alkyl selected fromphenoxy-C₁₋₆alkyl and naphthyloxy-C₁₋₆alkyl, the aryl portion of eachbeing optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is —C(O)—R⁸ and R⁸ is as defined herein.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is —CH₂—C(O)—R⁸ wherein R⁸ is as definedherein.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is:

C₁₋₆alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl and isopentyl;

C₁₋₆alkoxy-C₁₋₆alkyl selected from methoxymethyl, ethoxymethyl,2-(methoxy)-ethyl, 2-(ethoxy)-ethyl, 3-(methoxy)-propyl,3-(ethoxy)-propyl, 3-methoxy-3-methyl-butyl, 4-methoxy-butyl, or4-methoxy-4-methyl-pentyl;

C₁₋₆alkylsulfanyl-C₁₋₆alkyl selected from methylsulfanylmethyl,ethylsulfanylmethyl, 2-(methylsulfanyl)-ethyl, 2-(ethylsulfanyl)-ethyl,3-(methylsulfanyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfanyl-3-methyl-butyl, 4-methanesulfanyl-butyl, and4-methylsulfanyl-4-methyl-pentyl;

C₁₋₆alkylsulfonyl-C₁₋₆alkyl selected from methylsulfonylmethyl,ethylsulfanylmethyl, 2-(methylsulfonyl)-ethyl, 2-(ethylsulfonyl)-ethyl,3-(methylsulfonyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfonyl-3-methyl-butyl, 4-methanesulfonyl-butyl, and4-methylsulfonyl-4-methyl-pentyl;

hydroxy-C₁₋₆alkyl selected from hydroxymethyl, 2-hydroxy-ethyl,3-hydroxy-propyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl,3-hydroxy-3-methylbutyl, 4-hydroxy-4-methylpentyl,2-hydroxy-2-ethyl-propyl, 3-hydroxy-3-ethylbutyl and4-hydroxy-4-ethylpentyl;

amino-C₁₋₆alkyl selected from amino-methyl, 2-amino-ethyl,3-amino-propyl, 2-amino-propyl, 2-amino-2-methyl-propyl,3-amino-3-methylbutyl, 4-amino-4-methylpentyl, 2-amino-2-ethyl-propyl,3-amino-3-ethylbutyl and 4-amino-4-ethylpentyl;

N—C₁₋₆alkyl-amino-C₁₋₆alkyl selected from N-methylaminomethyl,2-(N-methylamino)-ethyl, 3-(N-methylamino)-propyl,2-(N-methylamino)-propyl, 2-(N-methylamino)-2-methyl-propyl,3-(N-methylamino)-3-methylbutyl, 4-(N-methylamino)-4-methylpentyl,2-(N-methylamino)-2-ethyl-propyl, 3-(-methylamino)-3-ethylbutyl4-(N-methylamino)-4-ethylpentyl, N-ethylaminomethyl,2-(N-ethylamino)-ethyl, 3-(N-ethylamino)-propyl,2-(N-ethylamino)-propyl, 2-(N-ethylamino)-2-methyl-propyl,3-(N-ethylamino)-3-methylbutyl, 4-(N-ethylamino)-4-methylpentyl,2-(N-ethylamino)-2-ethyl-propyl, 3-(N-ethylamino)-3-ethylbutyl, and4-(N-ethylamino)-4-ethylpentyl;

N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl selected from N,N-dimethylaminomethyl,2-(N,N-dimethylamino)-ethyl, 3-(N,N-dimethylamino)-propyl,2-(N,N-dimethylamino)-propyl, 2-(N,N-dimethylamino)-2-methyl-propyl,3-(N,N-dimethylamino)-3-methylbutyl,4-(N,N-dimethylamino)-4-methylpentyl,2-(N,N-dimethylamino)-2-ethyl-propyl, 3-(N,N-dimethylamino)-3-ethylbutyl4-(N,N-dimethylamino)-4-ethylpentyl, N,N-diethylaminomethyl,2-(N,N-diethylamino)-ethyl, 3-(N,N-diethylamino)-propyl,2-(N,N-diethylamino)-propyl, 2-(N,N-diethylamino)-2-methyl-propyl,3-(N,N-diethylamino)-3-methylbutyl, 4-(N,N-diethylamino)-4-methylpentyl,2-(N,N-diethylamino)-2-ethyl-propyl, 3-(N,N-diethylamino)-3-ethylbutyl,and 4-(N,N-diethylamino)-4-ethylpentyl;

C₃₋₇cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, each optionally substituted;

aryl selected from optionally substituted phenyl, optionally substitutednaphth-1-yl and optionally substituted naphth-2-yl;

heteroaryl selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,pyrimidin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,thien-2-yl, thien-3-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl, each optionally substituted;

heterocyclyl selected from piperidin-1-yl, piperidin-4-yl,piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,1-oxo-thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl, pyran-4-yl,pyrrolidin-1-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 2-oxa-8-aza-spiro[4.5]decan-8-yl,2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl, and3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl, each optionally substituted;

C₃₋₇cycloalkyl-C₁₋₆alkyl selected from cyclopropyl-methyl,cyclobutyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl,cyclopropyl-ethyl, cyclobutyl-ethyl, cyclopentyl-ethyl,cyclohexyl-ethyl, 3-(cyclopropyl)-propyl, 3-(cyclobutyl)-propyl,3-(cyclopentyl)-propyl, and 3-(cyclohexyl)-propyl, the cycloalkylportion of each being optionally substituted;

heteroaryl-C₁₋₆alkyl selected from pyridin-2-ylmethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-2-ylmethyl,pyridazin-3-ylmethyl, pyridazin-4-ylmethyl, pyrazin-2-ylmethyl,furan-2-ylmethyl, furan-3-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl,pyrrol-1-ylmethyl, pyrrol-2-ylmethyl, pyrrol-3-ylmethyl,oxazol-2-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl,thiazol-2-ylmethyl, thiazol-4-ylmethyl, thiazol-5-ylmethyl,imidazol-1-ylmethyl, imidazol-2-ylmethyl, imidazol-4-ylmethyl,isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, isoxazol-5-ylmethyl,isothiazol-3-ylmethyl, isothiazol-4-ylmethyl, isothiazol-5-ylmethyl,pyridin-2-ylethyl, pyridin-3-ylethyl, pyridin-4-ylethyl,pyrimidin-2-ylethyl, pyridazin-3-ylethyl, pyridazin-4-ylethyl,pyrazin-2-ylethyl, furan-2-ylethyl, furan-3-ylethyl, thien-2-ylethyl,thien-3-ylethyl, pyrrol-1-ylethyl, pyrrol-2-ylethyl, pyrrol-3-ylethyl,oxazol-2-ylethyl, oxazol-4-ylethyl, oxazol-5-ylethyl, thiazol-2-ylethyl,thiazol-4-ylethyl, thiazol-5-ylethyl, imidazol-1-ylethyl,imidazol-2-ylethyl, imidazol-4-ylethyl, isoxazol-3-ylethyl,isoxazol-4-ylethyl, isoxazol-5-ylethyl, isothiazol-3-ylethyl,isothiazol-4-ylethyl, isothiazol-5-ylethyl, 3-(pyridin-2-yl)-propyl,3-(pyridin-3-yl)-propyl, 3-(pyridin-4-yl)-propyl,3-(pyrimidin-2-yl)-propyl, 3-(pyridazin-3-yl)-propyl,3-(pyridazin-4-yl)-propyl, 3-(pyrazin-2-yl)-propyl,3-(furan-2-yl)-propyl, 3-(furan-3-yl)-propyl, 3-(thien-2-yl)-propyl,3-(thien-3-yl)-propyl, 3-(pyrrol-1-yl)-propyl, 3-(pyrrol-2-yl)-propyl,3-(pyrrol-3-yl)-propyl, 3-(oxazol-2-yl)-propyl, 3-(oxazol-4-yl)-propyl,3-(oxazol-5-yl)-propyl, 3-(thiazol-2-yl)-propyl,3-(thiazol-4-yl)-propyl, 3-(thiazol-5-yl)-propyl,3-(imidazol-1-yl)-propyl, 3-(imidazol-2-yl)-propyl,3-(imidazol-4-yl)-propyl, 3-(isoxazol-3-yl)-propyl,3-(isoxazol-4-yl)-propyl, 3-(isoxazol-5-yl)-propyl,3-(isothiazol-3-yl)-propyl, 3-(isothiazol-4-yl)-propyl, and3-(isothiazol-5-yl)-propyl, the heteroaryl portion of each beingoptionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperidin-1-ylmethyl,piperidin-4-ylmethyl, piperazin-1-ylmethyl, morpholin-4-ylmethyl,thiomorpholin-4-ylmethyl, 1-oxo-thiomorpholin-4-ylmethyl,1,1-dioxo-thiomorpholin-4-ylmethyl, pyran-4-ylmethyl,pyrrolidin-1-ylmethyl, pyrrolidin-3-ylmethyl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,piperidin-1-ylethyl, piperidin-4-ylethyl, piperazin-1-ylethyl,morpholin-4-ylethyl, thiomorpholin-4-ylethyl,1-oxo-thiomorpholin-4-ylethyl, 1,1-dioxo-thiomorpholin-4-ylethyl,pyran-4-ylethyl, pyrrolidin-1-ylethyl, pyrrolidin-3-ylethyl,tetrahydrofuran-2-ylethyl, tetrahydrofuran-3-ylethyl,3-(piperidin-1-yl)-propyl, 3-(piperidin-4-yl)-propyl,3-(piperazin-1-yl)-propyl, 3-(morpholin-4-yl)-propyl,3-(thiomorpholin-4-yl)-propyl, 3-(1-oxo-thiomorpholin-4-yl)-propyl,3-(1,1-dioxo-thiomorpholin-4-yl)-propyl, 3-(pyran-4-yl)-propyl,pyrrolidin-1-yl)-propyl, 3-(pyrrolidin-3-yl)-propyl,3-(tetrahydrofuran-2-yl)-propyl, 3-(tetrahydrofuran-3-yl)-propyl,2-oxa-8-aza-spiro[4.5]decan-8-ylmethyl,2-oxa-5-aza-bicyclo[2.2.1]heptan-5-ylmethyl,3-oxa-8-aza-bicyclo[3.2.1]octan-8-ylmethyl, the heterocyclyl portion ofeach being optionally substituted; or

—C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy,N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,N—C₃₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy. Preferably in suchembodiments R⁸ is C₁₋₆alkyloxy, N—C₁₋₆alkyl-amino, orN,N-di-C₁₋₆alkyl-amino.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₁₋₆alkyl selected from methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl andisopentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₁₋₆alkoxy-C₁₋₆alkyl selected frommethoxymethyl, ethoxymethyl, 2-(methoxy)-ethyl, 2-(ethoxy)-ethyl,3-(methoxy)-propyl, 3-(ethoxy)-propyl, 3-methoxy-3-methyl-butyl,4-methoxy-butyl, or 4-methoxy-4-methyl-pentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₁₋₆alkylsulfanyl-C₁₋₆alkyl selected frommethylsulfanylmethyl, ethylsulfanylmethyl, 2-(methylsulfanyl)-ethyl,2-(ethylsulfanyl)-ethyl, 3-(methylsulfanyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfanyl-3-methyl-butyl, 4-methanesulfanyl-butyl, and4-methylsulfanyl-4-methyl-pentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₁₋₆alkylsulfonyl-C₁₋₄alkyl selected frommethylsulfonylmethyl, ethylsulfanylmethyl, 2-(methylsulfonyl)-ethyl,2-(ethylsulfonyl)-ethyl, 3-(methylsulfonyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfonyl-3-methyl-butyl, 4-methanesulfonyl-butyl, and4-methylsulfonyl-4-methyl-pentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is hydroxy-C₁₋₆alkyl selected fromhydroxymethyl, 2-hydroxy-ethyl, 3-hydroxy-propyl, 2-hydroxy-propyl,2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methylbutyl,4-hydroxy-4-methylpentyl, 2-hydroxy-2-ethyl-propyl,3-hydroxy-3-ethylbutyl and 4-hydroxy-4-ethylpentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is amino-C₁₋₆alkyl selected from amino-methyl,2-amino-ethyl, 3-amino-propyl, 2-amino-propyl, 2-amino-2-methyl-propyl,3-amino-3-methylbutyl, 4-amino-4-methylpentyl, 2-amino-2-ethyl-propyl,3-amino-3-ethylbutyl and 4-amino-4-ethylpentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is N—C₁₋₆alkyl-amino-C₁₋₆alkyl selected fromN-methylaminomethyl, 2-(N-methylamino)-ethyl, 3-(N-methylamino)-propyl,2-(N-methylamino)-propyl, 2-(N-methylamino)-2-methyl-propyl,3-(N-methylamino)-3-methylbutyl, 4-(N-methylamino)-4-methylpentyl,2-(N-methylamino)-2-ethyl-propyl, 3-(-methylamino)-3-ethylbutyl4-(N-methylamino)-4-ethylpentyl, N-ethylaminomethyl,2-(N-ethylamino)-ethyl, 3-(N-ethylamino)-propyl,2-(N-ethylamino)-propyl, 2-(N-ethylamino)-2-methyl-propyl,3-(N-ethylamino)-3-methylbutyl, 4-(N-ethylamino)-4-methylpentyl,2-(N-ethylamino)-2-ethyl-propyl, 3-(N-ethylamino)-3-ethylbutyl, and4-(N-ethylamino)-4-ethylpentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl selectedfrom N,N-dimethylaminomethyl, 2-(N,N-dimethylamino)-ethyl,3-(N,N-dimethylamino)-propyl, 2-(N,N-dimethylamino)-propyl,2-(N,N-dimethylamino)-2-methyl-propyl,3-(N,N-dimethylamino)-3-methylbutyl,4-(N,N-dimethylamino)-4-methylpentyl,2-(N,N-dimethylamino)-2-ethyl-propyl, 3-(N,N-dimethylamino)-3-ethylbutyl4-(N,N-dimethylamino)-4-ethylpentyl, N,N-diethylaminomethyl,2-(N,N-diethylamino)-ethyl, 3-(N,N-diethylamino)-propyl,2-(N,N-diethylamino)-propyl, 2-(N,N-diethylamino)-2-methyl-propyl,3-(N,N-diethylamino)-3-methylbutyl, 4-(N,N-diethylamino)-4-methylpentyl,2-(N,N-diethylamino)-2-ethyl-propyl, 3-(N,N-diethylamino)-3-ethylbutyl,and 4-(N,N-diethylamino)-4-ethylpentyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₃₋₇cycloalkyl selected from cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is aryl selected from optionally substitutedphenyl, optionally substituted naphth-1-yl and optionally substitutednaphth-2-yl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heteroaryl selected from pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, thien-2-yl, thien-3-yl, pyrrol-2-yl,pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl,isothiazol-4-yl, and isothiazol-5-yl, each optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, Ma, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heterocyclyl selected from piperidin-1-yl,piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,1-oxo-thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl, pyran-4-yl,pyrrolidin-1-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl andtetrahydrofuran-3-yl, each optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is C₃₋₇cycloalkyl-C₁₋₆alkyl selected fromcyclopropyl-methyl, cyclobutyl-methyl, cyclopentyl-methyl,cyclohexyl-methyl, cyclopropyl-ethyl, cyclobutyl-ethyl,cyclopentyl-ethyl, cyclohexyl-ethyl, 3-(cyclopropyl)-propyl,3-(cyclobutyl)-propyl, 3-(cyclopentyl)-propyl, and3-(cyclohexyl)-propyl, the cycloalkyl portion of each being optionallysubstituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heteroaryl-C₁₋₆alkyl selected frompyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl,pyrimidin-2-ylmethyl, pyridazin-3-ylmethyl, pyridazin-4-ylmethyl,pyrazin-2-ylmethyl, furan-2-ylmethyl, furan-3-ylmethyl,thien-2-ylmethyl, thien-3-ylmethyl, pyrrol-1-ylmethyl,pyrrol-2-ylmethyl, pyrrol-3-ylmethyl, oxazol-2-ylmethyl,oxazol-4-ylmethyl, oxazol-5-ylmethyl, thiazol-2-ylmethyl,thiazol-4-ylmethyl, thiazol-5-ylmethyl, imidazol-1-ylmethyl,imidazol-2-ylmethyl, imidazol-4-ylmethyl, isoxazol-3-ylmethyl,isoxazol-4-ylmethyl, isoxazol-5-ylmethyl, isothiazol-3-ylmethyl,isothiazol-4-ylmethyl, isothiazol-5-ylmethyl, pyridin-2-ylethyl,pyridin-3-ylethyl, pyridin-4-ylethyl, pyrimidin-2-ylethyl,pyridazin-3-ylethyl, pyridazin-4-ylethyl, pyrazin-2-ylethyl,furan-2-ylethyl, furan-3-ylethyl, thien-2-ylethyl, thien-3-ylethyl,pyrrol-1-ylethyl, pyrrol-2-ylethyl, pyrrol-3-ylethyl, oxazol-2-ylethyl,oxazol-4-ylethyl, oxazol-5-ylethyl, thiazol-2-ylethyl,thiazol-4-ylethyl, thiazol-5-ylethyl, imidazol-1-ylethyl,imidazol-2-ylethyl, imidazol-4-ylethyl, isoxazol-3-ylethyl,isoxazol-4-ylethyl, isoxazol-5-ylethyl, isothiazol-3-ylethyl,isothiazol-4-ylethyl, isothiazol-5-ylethyl, 3-(pyridin-2-yl)-propyl,3-(pyridin-3-yl)-propyl, 3-(pyridin-4-yl)-propyl,3-(pyrimidin-2-yl)-propyl, 3-(pyridazin-3-yl)-propyl,3-(pyridazin-4-yl)-propyl, 3-(pyrazin-2-yl)-propyl,3-(furan-2-yl)-propyl, 3-(furan-3-yl)-propyl, 3-(thien-2-yl)-propyl,3-(thien-3-yl)-propyl, 3-(pyrrol-1-yl)-propyl, 3-(pyrrol-2-yl)-propyl,3-(pyrrol-3-yl)-propyl, 3-(oxazol-2-yl)-propyl, 3-(oxazol-4-yl)-propyl,3-(oxazol-5-yl)-propyl, 3-(thiazol-2-yl)-propyl,3-(thiazol-4-yl)-propyl, 3-(thiazol-5-yl)-propyl,3-(imidazol-1-yl)-propyl, 3-(imidazol-2-yl)-propyl,3-(imidazol-4-yl)-propyl, 3-(isoxazol-3-yl)-propyl,3-(isoxazol-4-yl)-propyl, 3-(isoxazol-5-yl)-propyl,3-(isothiazol-3-yl)-propyl, 3-(isothiazol-4-yl)-propyl, and3-(isothiazol-5-yl)-propyl, the heteroaryl portion of each beingoptionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heterocyclyl-C₁₋₆alkyl selected frompiperidin-1-ylmethyl, piperidin-4-ylmethyl, piperazin-1-ylmethyl,morpholin-4-ylmethyl, thiomorpholin-4-ylmethyl,1-oxo-thiomorpholin-4-ylmethyl, 1,1-dioxo-thiomorpholin-4-ylmethyl,pyran-4-ylmethyl, pyrrolidin-1-ylmethyl, pyrrolidin-3-ylmethyl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,piperidin-1-ylethyl, piperidin-4-ylethyl, piperazin-1-ylethyl,morpholin-4-ylethyl, thiomorpholin-4-ylethyl,1-oxo-thiomorpholin-4-ylethyl, 1,1-dioxo-thiomorpholin-4-ylethyl,pyran-4-ylethyl, pyrrolidin-1-ylethyl, pyrrolidin-3-ylethyl,tetrahydrofuran-2-ylethyl, tetrahydrofuran-3-ylethyl,3-(piperidin-1-yl)-propyl, 3-(piperidin-4-yl)-propyl,3-(piperazin-1-yl)-propyl, 3-(morpholin-4-yl)-propyl,3-(thiomorpholin-4-yl)-propyl, 3-(1-oxo-thiomorpholin-4-yl)-propyl,3-(1,1-dioxo-thiomorpholin-4-yl)-propyl, 3-(pyran-4-yl)-propyl,pyrrolidin-1-yl)-propyl, 3-(pyrrolidin-3-yl)-propyl,3-(tetrahydrofuran-2-yl)-propyl, 3-(tetrahydrofuran-3-yl)-propyl,2-oxa-8-aza-spiro[4.5]decan-8-ylmethyl,2-oxa-5-aza-bicyclo[2.2.1]heptan-5-ylmethyl,3-oxa-8-aza-bicyclo[3.2.1]octan-8-ylmethyl, the heterocyclyl portion ofeach being optionally substituted.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is —C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl,C₁₋₆alkyloxy, N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,N—C₃₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is CH₂—C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl,C₁₋₆alkyloxy, N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,N—C₃₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is:

hetero-C₁₋₆alkyl selected from hydroxymethyl,2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl;

heterocyclyl-C₁₋₆alkyl selected from morpholin-4-ylmethyl,piperidin-1-ylmethyl, piperazin-1-ylmethyl, thiomorpholin-1-ylmethyl,4-methanesulfonyl-piperazin-1-ylmethyl, 4-acetyl-piperazin-1-ylmethyl,4-acetyl-3-methyl-piperazin-1-ylmethyl, 3-oxy-piperazin-1-ylmethyl,4-methanesulfonyl-piperidin-1-ylmethyl, 4-fluoropiperidin-1-ylmethyl,4,4-difluoropiperidin-1-ylmethyl, 3-fluoro-piperidin-1-ylmethyl,4-methoxy-piperidin-1-ylmethyl, 3-methoxy-piperidin-1-ylmethyl,4-hydroxy-piperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,4-methoxy-3-fluoro-piperidin-1-ylmethyl,2,6-dimethyl-morpholin-4-ylmethyl, 1-oxy-thiomorpholin-4-ylmethyl and1,1-dioxy-thiomorpholin-4-ylmethyl; or

heteroaryl selected from pyrazin-2-yl, pyridazin-3-yl and thiazol-2-yl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is hetero-C₁₋₆alkyl selected fromhydroxymethyl, 2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heterocyclyl-C₁₋₆alkyl selected frommorpholin-4-ylmethyl, piperidin-1-ylmethyl, piperazin-1-ylmethyl,thiomorpholin-1-ylmethyl, 4-methanesulfonyl-piperazin-1-ylmethyl,4-acetyl-piperazin-1-ylmethyl, 4-acetyl-3-methyl-piperazin-1-ylmethyl,3-oxy-piperazin-1-ylmethyl, 4-methanesulfonyl-piperidin-1-ylmethyl,4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,3-fluoro-piperidin-1-ylmethyl, 4-methoxy-piperidin-1-ylmethyl,3-methoxy-piperidin-1-ylmethyl, 4-hydroxy-piperidin-1-ylmethyl,3-hydroxypiperidin-1-ylmethyl, 4-methoxy-3-fluoro-piperidin-1-ylmethyl,2,6-dimethyl-morpholin-4-ylmethyl, 1-oxy-thiomorpholin-4-ylmethyl and1,1-dioxy-thiomorpholin-4-ylmethyl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is heteroaryl selected from pyrazin-2-yl,pyridazin-3-yl and thiazol-2-yl.

In certain embodiments of formula I, R¹ is: tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and

R⁵ is:

-   -   C₁₋₆alkyl;    -   C₁₋₆alkyloxy-C₁₋₆alkyl;    -   hydroxy-C₁₋₆alkyl;    -   C₁₋₆alkylsulfanyl-C₁₋₆alkyl;    -   C₁₋₆alkylsulfonyl-C₁₋₆alkyl;    -   amino-C₁₋₆alkyl;    -   N—C₁₋₆alkyl-amino-C₁₋₆alkyl;    -   N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl;    -   C₃₋₇cycloalkyl;    -   optionally substituted phenyl;    -   optionally substituted naphthyl;    -   optionally substituted pyridinyl;    -   optionally substituted pyrazinyl;    -   optionally substituted pyridizinyl;    -   optionally substituted thiazolyl;    -   optionally substituted piperidinyl-C₁₋₆alkyl;    -   optionally substituted piperazinyl-C₁₋₆alkyl;    -   optionally substituted morpholinyl-C₁₋₆alkyl;    -   optionally substituted thiomorpholinyl-C₁₋₆alkyl;    -   optionally substituted pyrrolidinyl-C₁₋₆alkyl; or    -   —C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy,        N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,        N—C₃₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy. When R⁸ is        heterocyclyl, preferred heterocyclyl include morpholinyl and        piperidinyl, each optionally substituted.

In certain embodiments of formula I: R′ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is C₁₋₆alkyl. In such embodiments R⁵ may be C₁₋₆alkylselected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl and isopentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is C₁₋₆alkyloxy-C₁₋₆alkyl. In such embodiments R⁵ may beC₁₋₆alkyloxy-C₁₋₆alkyl selected from methoxymethyl, ethoxymethyl,2-(methoxy)-ethyl, 2-(ethoxy)-ethyl, 3-(methoxy)-propyl,3-(ethoxy)-propyl, 3-methoxy-3-methyl-butyl, 4-methoxy-butyl, and4-methoxy-4-methyl-pentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is C₁₋₆alkylsulfanyl-C₁₋₆alkyl. In such embodiments R⁵may be C₁₋₆alkylsulfanyl-C₁₋₆alkyl selected from methylsulfanylmethyl,ethylsulfanylmethyl, 2-(methylsulfanyl)-ethyl, 2-(ethylsulfanyl)-ethyl,3-(methylsulfanyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfanyl-3-methyl-butyl, 4-methanesulfanyl-butyl, and4-methylsulfanyl-4-methyl-pentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is C₁₋₆alkylsulfonyl-C₁₋₆alkyl. In such embodiments R⁵may be C₁₋₆alkylsulfonyl-C₁₋₆alkyl selected from methylsulfonylmethyl,ethylsulfanylmethyl, 2-(methylsulfonyl)-ethyl, 2-(ethylsulfonyl)-ethyl,3-(methylsulfonyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfonyl-3-methyl-butyl, 4-methanesulfonyl-butyl, and4-methylsulfonyl-4-methyl-pentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is hydroxy-C₁₋₆alkyl. In such embodiments R⁵ may behydroxy-C₁₋₆alkyl selected from hydroxymethyl, 2-hydroxy-ethyl,3-hydroxy-propyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl,3-hydroxy-3-methylbutyl, 4-hydroxy-4-methylpentyl,2-hydroxy-2-ethyl-propyl, 3-hydroxy-3-ethylbutyl and4-hydroxy-4-ethylpentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is R⁵ is amino-C₁₋₆alkyl. In such embodiments, R⁵ may beamino-C₁₋₆alkyl selected from amino-methyl, 2-amino-ethyl,3-amino-propyl, 2-amino-propyl, 2-amino-2-methyl-propyl,3-amino-3-methylbutyl, 4-amino-4-methylpentyl, 2-amino-2-ethyl-propyl,3-amino-3-ethylbutyl and 4-amino-4-ethylpentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is R⁵ is N—C₁₋₆alkyl-amino-C₁₋₆alkyl. In such embodimentsR⁵ may be N—C₁₋₆alkyl-amino-C₁₋₆alkyl selected from N-methylaminomethyl,2-(N-methylamino)-ethyl, 3-(N-methylamino)-propyl,2-(N-methylamino)-propyl, 2-(N-methylamino)-2-methyl-propyl,3-(N-methylamino)-3-methylbutyl, 4-(N-methylamino)-4-methylpentyl,2-(N-methylamino)-2-ethyl-propyl, 3-(-methylamino)-3-ethylbutyl4-(N-methylamino)-4-ethylpentyl, N-ethylaminomethyl,2-(N-ethylamino)-ethyl, 3-(N-ethylamino)-propyl,2-(N-ethylamino)-propyl, 2-(N-ethylamino)-2-methyl-propyl,3-(N-ethylamino)-3-methylbutyl, 4-(N-ethylamino)-4-methylpentyl,2-(N-ethylamino)-2-ethyl-propyl, 3-(N-ethylamino)-3-ethylbutyl, and4-(N-ethylamino)-4-ethylpentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl. In such embodimentsR⁵ may be N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl selected fromN,N-dimethylaminomethyl, 2-(N,N-dimethylamino)-ethyl,3-(N,N-dimethylamino)-propyl, 2-(N,N-dimethylamino)-propyl,2-(N,N-dimethylamino)-2-methyl-propyl,3-(N,N-dimethylamino)-3-methylbutyl,4-(N,N-dimethylamino)-4-methylpentyl,2-(N,N-dimethylamino)-2-ethyl-propyl, 3-(N,N-dimethylamino)-3-ethylbutyl4-(N,N-dimethylamino)-4-ethylpentyl, N,N-diethylaminomethyl,2-(N,N-diethylamino)-ethyl, 3-(N,N-diethylamino)-propyl,2-(N,N-diethylamino)-propyl, 2-(N,N-diethylamino)-2-methyl-propyl,3-(N,N-diethylamino)-3-methylbutyl, 4-(N,N-diethylamino)-4-methylpentyl,2-(N,N-diethylamino)-2-ethyl-propyl, 3-(N,N-diethylamino)-3-ethylbutyl,and 4-(N,N-diethylamino)-4-ethylpentyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted phenyl. In such embodiments R⁵may be phenyl optionally substituted once, twice or three times withC₁₋₆alkyl, C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl,C₁₋₆alkylsulfonyl or cyano. In certain embodiments R⁵ is phenylsubstituted once or twice with halo, cyano, trifluoromethyl,methanesulfonyl, methoxy, or methyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted pyridinyl. In such embodimentsR⁵ may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl each optionallysubstituted once, twice or three times with C₁₋₆alkyl, C₁₋₆alkyloxy,halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano. Incertain embodiments R⁵ is pyridin-2-yl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted pyrazinyl. In certainembodiments R⁵ may be pyrazin-2-yl optionally substituted once, twice orthree times with C₁₋₆alkyl, C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl,hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano. In certain embodiments R⁵is pyrazin-2-yl

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted pyrimidinyl. In certainembodiments R⁵ may be pyrimidin-2-yl optionally substituted once, twiceor three times with C₁₋₆alkyl, C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl,hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano. In certain embodiments R⁵is pyrimidin-2-yl

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl orC₃₋₆-cycloalkyl; R² is phenyl substituted once or twice with fluoro,chloro or methyl; R³ and R⁶ are hydrogen; R⁴ is methyl; and R⁵ isoptionally substituted pyridazinyl. In certain embodiments R⁵ may bepyridazin-3-yl optionally substituted once, twice or three times withC₁₋₆alkyl, C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl,C₁₋₆alkylsulfonyl or cyano. In certain embodiments R⁵ is pyridazin-3-yl

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted thiazolyl. In certainembodiments R⁵ may be thiazolyl-2-yl optionally substituted once ortwice with C₁₋₆alkyl, C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl,hetero-C₁₋₆alkyl, C₁. 6alkylsulfonyl or cyano.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted piperidinyl-C₁₋₆alkyl. In suchembodiments R⁵ may be piperidin-1-ylmethyl,4-hydroxy-piperidinyl-1-ylmethyl, 4-methoxy-piperidin-1-ylmethyl,4-methanesulfonyl-piperidin-1-ylmethyl, 4-fluoro-piperidin-1-ylmethyl or4,4-difluoropiperidin-1-ylmethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted piperazinyl-C₁₋₆alkyl. In suchembodiments R⁵ may be piperazin-1-ylmethyl,4-methyl-piperazin-1-ylmethyl, 4-methanesulfonyl-piperazin-1-ylmethyl,4-acetyl-piperazin-1-ylmethyl, 3-methyl-piperazin-1-ylmethyl,3,4-dimethyl-piperazin-1-ylmethyl,3-methyl-4-methanesulfonyl-piperazin-1-ylmethyl,3-methyl-4-acetyl-piperazin-1-ylmethyl,3,5-dimethyl-piperazin-1-ylmethyl, 3,4,5-trimethyl-piperazin-1-ylmethyl,3,5-dimethyl-4-methanesulfonyl-piperazin-1-ylmethyl,3,5-dimethyl-4-acetyl-piperazin-1-ylmethyl,4-(pyrimidin-2-yl)-piperazin-1-ylmethyl or3-methoxy-piperazin-1-ylmethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted morpholinyl-C₁₋₆alkyl. In suchembodiments R⁵ may be morpholin-4-ylmethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted thiomorpholinyl-C₁₋₆alkyl. Insuch embodiments R⁵ may be thiomorpholin-4-ylmethyl,1-oxo-thiomorpholin-4-ylmethyl or 1,1,-dioxo-thiomorpholin-4-ylmethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is optionally substituted pyrrolidinyl-C₁₋₆alkyl. In suchembodiments R⁵ may be pyrrolidin-1-ylmethyl or3-hydroxypyrrolidin-1-ylmethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is —C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy,N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,N—C₃₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is —CH₂—C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy,N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,N—C₃₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy.

In certain embodiments of formula I, le is: tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl orC₃₋₆-cycloalkyl; R² is phenyl substituted once or twice with fluoro,chloro or methyl; R³ and R⁶ are hydrogen; R⁴ is methyl; and R⁵ is:

hetero-C₁₋₆alkyl selected from hydroxymethyl,2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl;

heterocyclyl-C₁₋₆alkyl selected from morpholin-4-ylmethyl,piperidin-1-ylmethyl, piperazin-1-ylmethyl, thiomorpholin-1-ylmethyl,4-methanesulfonyl-piperazin-1-ylmethyl, 4-acetyl-piperazin-1-ylmethyl,4-acetyl-3-methyl-piperazin-1-ylmethyl, 3-oxy-piperazin-1-ylmethyl,4-methanesulfonyl-piperidin-1-ylmethyl, 4-fluoropiperidin-1-ylmethyl,4,4-difluoropiperidin-1-ylmethyl, 3-fluoro-piperidin-1-ylmethyl,4-methoxy-piperidin-1-ylmethyl, 3-methoxy-piperidin-1-ylmethyl,4-hydroxy-piperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,4-methoxy-3-fluoro-piperidin-1-ylmethyl,2,6-dimethyl-morpholin-4-ylmethyl, 1-oxy-thiomorpholin-4-ylmethyl and1,1-dioxy-thiomorpholin-4-ylmethyl; or

heteroaryl selected from pyrazin-2-yl, pyridazin-3-yl and thiazol-2-yl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is hetero-C₁₋₆alkyl selected from hydroxymethyl,2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is heterocyclyl-C₁₋₆alkyl selected frommorpholin-4-ylmethyl, piperidin-1-ylmethyl, piperazin-1-ylmethyl,thiomorpholin-1-ylmethyl, 4-methanesulfonyl-piperazin-1-ylmethyl,4-acetyl-piperazin-1-ylmethyl, 4-acetyl-3-methyl-piperazin-1-ylmethyl,3-oxy-piperazin-1-ylmethyl, 4-methanesulfonyl-piperidin-1-ylmethyl,4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,3-fluoro-piperidin-1-ylmethyl, 4-methoxy-piperidin-1-ylmethyl,3-methoxy-piperidin-1-ylmethyl, 4-hydroxy-piperidin-1-ylmethyl,3-hydroxypiperidin-1-ylmethyl, 4-methoxy-3-fluoro-piperidin-1-ylmethyl,2,6-dimethyl-morpholin-4-ylmethyl, 1-oxy-thiomorpholin-4-ylmethyl and1,1-dioxy-thiomorpholin-4-ylmethyl.

In certain embodiments of formula I, R¹ is; tetrazol-1-yl optionallysubstituted at the 5-position with C₁₋₆alkyl, halo-C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or C₃₋₆-cycloalkyl; R² is phenyl substituted onceor twice with fluoro, chloro or methyl; R³ and R⁶ are hydrogen; R⁴ ismethyl; and R⁵ is heteroaryl selected from pyrazin-2-yl, pyridazin-3-yland thiazol-2-yl.

In certain embodiments of formula IIa, IIIb or IIIc, R¹¹ is fluoro,chloro or methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl; and

R⁵ is:

-   -   C₃₋₆alkyl;    -   C₁₋₆alkyloxy-C₁₋₆alkyl;    -   hydroxy-C₁₋₆alkyl;    -   C₁₋₆alkylsulfanyl-C₁₋₆alkyl;    -   C₁₋₆alkylsulfonyl-C₁₋₆alkyl;    -   amino-C₁₋₆alkyl;    -   N—C₁₋₆alkyl-amino-C₁₋₆alkyl;    -   N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl;    -   C₃₋₇cycloalkyl;    -   optionally substituted phenyl;    -   optionally substituted naphthyl;    -   optionally substituted pyridinyl;    -   optionally substituted pyrazinyl;    -   optionally substituted pyridizinyl;    -   optionally substituted thiazolyl;    -   optionally substituted piperidinyl-C₁₋₆alkyl;    -   optionally substituted piperazinyl-C₁₋₆alkyl;    -   optionally substituted morpholinyl-C₁₋₆alkyl;    -   optionally substituted thiomorpholinyl-C₁₋₆alkyl;

optionally substituted pyrrolidinyl-C₁₋₆alkyl; or

-   -   —C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy,        N—C₁₋₆alkyl-amino, N,N-di-C₁₋₆alkyl-amino, heterocyclyl,        N—C₁₋₆cycloalkyl-amino or C₃₋₆cycloalkyloxy.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is C₁₋₆alkyl. Insuch embodiments R⁵ may be C₁₋₆alkyl selected from methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl andisopentyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ isC₁₋₆alkyloxy-C₁₋₆alkyl. In such embodiments R⁵ may beC₁₋₆alkyloxy-C₁₋₆alkyl selected from methoxymethyl, ethoxymethyl,2-(methoxy)-ethyl, 2-(ethoxy)-ethyl, 3-(methoxy)-propyl,3-(ethoxy)-propyl, 3-methoxy-3-methyl-butyl, 4-methoxy-butyl, and4-methoxy-4-methyl-pentyl.

In certain embodiments of formula IIa or IIb, R¹¹ is fluoro, chloro ormethyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ isC₁₋₆alkylsulfanyl-C₁₋₆alkyl. In such embodiments R⁵ may beC₁₋₆alkylsulfanyl-C₁₋₆alkyl selected from methylsulfanylmethyl,ethylsulfanylmethyl, 2-(methylsulfanyl)-ethyl, 2-(ethylsulfanyl)-ethyl,3-(methylsulfanyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfanyl-3-methyl-butyl, 4-methanesulfanyl-butyl, and4-methylsulfanyl-4-methyl-pentyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ isC₁₋₆alkylsulfonyl-C₁₋₆alkyl. In such embodiments R⁵ may beC₁₋₆alkylsulfonyl-C₁₋₆alkyl selected from methylsulfonylmethyl,ethylsulfanylmethyl, 2-(methylsulfonyl)-ethyl, 2-(ethylsulfonyl)-ethyl,3-(methylsulfonyl)-propyl, 3-(ethanyl)-propyl,3-methanesulfonyl-3-methyl-butyl, 4-methanesulfonyl-butyl, and4-methylsulfonyl-4-methyl-pentyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ ishydroxy-C₁₋₆alkyl. In such embodiments R⁵ may be hydroxy-C₁₋₆alkylselected from hydroxymethyl, 2-hydroxy-ethyl, 3-hydroxy-propyl,2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methylbutyl,4-hydroxy-4-methylpentyl, 2-hydroxy-2-ethyl-propyl,3-hydroxy-3-ethylbutyl and 4-hydroxy-4-ethylpentyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ isamino-C₁₋₆alkyl. In such embodiments, R⁵ may be amino-C₁₋₆alkyl selectedfrom amino-methyl, 2-amino-ethyl, 3-amino-propyl, 2-amino-propyl,2-amino-2-methyl-propyl, 3-amino-3-methylbutyl, 4-amino-4-methylpentyl,2-amino-2-ethyl-propyl, 3-amino-3-ethylbutyl and 4-amino-4-ethylpentyl.

In certain embodiments of formula IIa, IIIb or IIIc, R¹¹ is fluoro,chloro or methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C_(1/6)alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ isN—C₁₋₆alkyl-amino-C₁₋₆alkyl. In such embodiments R⁵ may beN—C₁₋₆alkyl-amino-C₁₋₆alkyl selected from N-methylaminomethyl,2-(N-methylamino)-ethyl, 3-(N-methylamino)-propyl,2-(N-methylamino)-propyl, 2-(N-methylamino)-2-methyl-propyl,3-(N-methylamino)-3-methylbutyl, 4-(N-methylamino)-4-methylpentyl,2-(N-methylamino)-2-ethyl-propyl, 3-(-methylamino)-3-ethylbutyl4-(N-methylamino)-4-ethylpentyl, N-ethylaminomethyl,2-(N-ethylamino)-ethyl, 3-(N-ethylamino)-propyl,2-(N-ethylamino)-propyl, 2-(N-ethylamino)-2-methyl-propyl,3-(N-ethylamino)-3-methylbutyl, 4-(N-ethylamino)-4-methylpentyl,2-(N-ethylamino)-2-ethyl-propyl, 3-(N-ethylamino)-3-ethylbutyl, and4-(N-ethylamino)-4-ethylpentyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ isN,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl. In such embodiments R⁵ may beN,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl selected from N,N-dimethylaminomethyl,2-(N,N-dimethylamino)-ethyl, 3-(N,N-dimethylamino)-propyl,2-(N,N-dimethylamino)-propyl, 2-(N,N-dimethylamino)-2-methyl-propyl,3-(N,N-dimethylamino)-3-methylbutyl,4-(N,N-dimethylamino)-4-methylpentyl,2-(N,N-dimethylamino)-2-ethyl-propyl, 3-(N,N-dimethylamino)-3-ethylbutyl4-(N,N-dimethylamino)-4-ethylpentyl, N,N-diethylaminomethyl,2-(N,N-diethylamino)-ethyl, 3-(N,N-diethylamino)-propyl,2-(N,N-diethylamino)-propyl, 2-(N,N-diethylamino)-2-methyl-propyl,3-(N,N-diethylamino)-3-methylbutyl, 4-(N,N-diethylamino)-4-methylpentyl,2-(N,N-diethylamino)-2-ethyl-propyl, 3-(N,N-diethylamino)-3-ethylbutyl,and 4-(N,N-diethylamino)-4-ethylpentyl.

In certain embodiments of formula IIa or IIb, R¹¹ is fluoro, chloro ormethyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionally substitutedphenyl. In such embodiments R⁵ may be phenyl optionally substitutedonce, twice or three times with C₁₋₆alkyl, C₁₋₆alkyloxy, halo,C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano. In certainembodiments R⁵ is phenyl substituted once or twice with halo, cyano,trifluoromethyl, methanesulfonyl, methoxy, or methyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted pyridinyl. In such embodiments R⁵ may be pyridin-2-yl,pyridin-3-yl or pyridin-4-yl each optionally substituted once, twice orthree times with C₁₋₆alkyl, C₁₋₆alkyloxy, halo, hetero-C₁₋₆alkyl,C₁₋₆alkylsulfonyl or cyano. In certain embodiments R⁵ is pyridin-2-yl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted pyrazinyl. In certain embodiments R⁵ may be pyrazin-2-yloptionally substituted once, twice or three times with C₁₋₆alkyl,C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonylor cyano. In certain embodiments R⁵ is pyrazin-2-yl

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted pyrimidinyl. In certain embodiments R⁵ may be pyrimidin-2-yloptionally substituted once, twice or three times with C₁₋₆alkyl,C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl, hetero-6alkyl, C₁₋₆alkylsulfonyl orcyano. In certain embodiments R⁵ is pyrimidin-2-yl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted pyridazinyl. In certain embodiments R⁵ may be pyridazin-3-yloptionally substituted once, twice or three times with C₁₋₆alkyl,C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonylor cyano. In certain embodiments R⁵ is pyridazin-3-yl

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted thiazolyl. In certain embodiments R⁵ may be thiazolyl-2-yloptionally substituted once or twice with C₁₋₆alkyl, C₁₋₆alkyloxy, halo,C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted piperidinyl-C₁₋₆alkyl. In such embodiments R⁵ may bepiperidin-1-ylmethyl, 4-hydroxy-piperidinyl-1-ylmethyl,4-methoxy-piperidin-1-ylmethyl, 4-methanesulfonyl-piperidin-1-ylmethyl,4-fluoro-piperidin-1-ylmethyl or 4,4-difluoropiperidin-1-ylmethyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted piperazinyl-C₁₋₆alkyl. In such embodiments R⁵ may bepiperazin-1-ylmethyl, 4-methyl-piperazin-1-ylmethyl,4-methanesulfonyl-piperazin-1-ylmethyl, 4-acetyl-piperazin-1-ylmethyl,3-methyl-piperazin-1-ylmethyl, 3,4-dimethyl-piperazin-1-ylmethyl,3-methyl-4-methanesulfonyl-piperazin-1-ylmethyl,3-methyl-4-acetyl-piperazin-1-ylmethyl,3,5-dimethyl-piperazin-1-ylmethyl, 3,4,5-trimethyl-piperazin-1-ylmethyl,3,5-dimethyl-4-methanesulfonyl-piperazin-1-ylmethyl,3,5-dimethyl-4-acetyl-piperazin-1-ylmethyl,4-(pyrimidin-2-yl)-piperazin-1-ylmethyl or3-methoxy-piperazin-1-ylmethyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted morpholinyl-C₁₋₆alkyl. In such embodiments R⁵ may bemorpholin-4-ylmethyl.

In certain embodiments of formula IIa, IIb or IIc; R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen orC₁₋₆alkyl, and R⁵ is optionally substituted thiomorpholinyl-C₁₋₆alkyl.In such embodiments R⁵ may be thiomorpholin-4-ylmethyl,1-oxo-thiomorpholin-4-ylmethyl or 1,1,-dioxo-thiomorpholin-4-ylmethyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is optionallysubstituted pyrrolidinyl-C₁₋₆alkyl. In such embodiments R⁵ may bepyrrolidin-1-ylmethyl or 3-hydroxypyrrolidin-1-ylmethyl.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is —C(O)—R⁸wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy, N—C₁₋₆alkyl-amino,N,N-di-C₁₋₆alkyl-amino, heterocyclyl, N—C₃₋₆cycloalkyl-amino orC₃₋₆cycloalkyloxy.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is —CH₂—C(O)—R⁸wherein R⁸ is C₁₋₆alkyl, C₁₋₆alkyloxy, N—C₁₋₆alkyl-amino,N,N-di-C₁₋₆alkyl-amino, heterocyclyl, N—C₃₋₆cycloalkyl-amino orC₃₋₆cycloalkyloxy.

In certain embodiments of formula IIa, IIb or IIc, R¹¹ is fluoro, chloroor methyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is:

hetero-C₁₋₆alkyl selected from hydroxymethyl,2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl;

heterocyclyl-C₁₋₆alkyl selected from morpholin-4-ylmethyl,piperidin-1-ylmethyl, piperazin-1-ylmethyl, thiomorpholin-1-ylmethyl,4-methanesulfonyl-piperazin-1-ylmethyl, 4-acetyl-piperazin-1-ylmethyl,4-acetyl-3-methyl-piperazin-1-ylmethyl, 3-oxy-piperazin-1-ylmethyl,4-methanesulfonyl-piperidin-1-ylmethyl, 4-fluoropiperidin-1-ylmethyl,4,4-difluoropiperidin-1-ylmethyl, 3-fluoro-piperidin-1-ylmethyl,4-methoxy-piperidin-1-ylmethyl, 3-methoxy-piperidin-1-ylmethyl,4-hydroxy-piperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,4-methoxy-3-fluoro-piperidin-1-ylmethyl,2,6-dimethyl-morpholin-4-ylmethyl, 1-oxy-thiomorpholin-4-ylmethyl and1,1-dioxy-thiomorpholin-4-ylmethyl; or

heteroaryl selected from pyrazin-2-yl, pyridazin-3-yl and thiazol-2-yl.

In certain embodiments of formula IIa or IIb, R¹¹ is fluoro, chloro ormethyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is hetero-C₁₋₆alkyl selectedfrom hydroxymethyl, 2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl.

In certain embodiments of formula IIa or IIb, R¹¹ is fluoro, chloro ormethyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is heterocyclyl-C₁₋₆alkylselected from morpholin-4-ylmethyl, piperidin-1-ylmethyl,piperazin-1-ylmethyl, thiomorpholin-1-ylmethyl,4-methanesulfonyl-piperazin-1-ylmethyl, 4-acetyl-piperazin-1-ylmethyl,4-acetyl-3-methyl-piperazin-1-ylmethyl, 3-oxy-piperazin-1-ylmethyl,4-methanesulfonyl-piperidin-1-ylmethyl, 4-fluoropiperidin-1-ylmethyl,4,4-difluoropiperidin-1-ylmethyl, 3-fluoro-piperidin-1-ylmethyl,4-methoxy-piperidin-1-ylmethyl, 3-methoxy-piperidin-1-ylmethyl,4-hydroxy-piperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,4-methoxy-3-fluoro-piperidin-1-ylmethyl,2,6-dimethyl-morpholin-4-ylmethyl, 1-oxy-thiomorpholin-4-ylmethyl and1,1-dioxy-thiomorpholin-4-ylmethyl.

In certain embodiments of formula IIa or IIb, R¹¹ is fluoro, chloro ormethyl, R¹² is hydrogen, fluoro or chloro, R¹³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl or cyclopropyl, and R⁵ is heteroaryl selected frompyrazin-2-yl, pyridazin-3-yl and thiazol-2-yl.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is:

wherein:

n is 0, 1 or 2;

R^(c) and R^(d) each independently is hydrogen or C₁₋₆alkyl;

R^(e) is hydrogen, C₁₋₆alkyl, acetyl or C₁₋₆alkyl-sulfonyl;

R^(f) and R^(g) each independently is hydrogen or C₁₋₆alkyl;

R^(h) and R^(i) each independently is hydrogen, C₁₋₆alkyl, fluoro,hydroxy or C₁₋₆alkyloxy;

R^(j) and R^(k) each independently is hydrogen or C₁₋₆alkyl; and

R^(m), R^(o), R^(p), R^(q) and R^(r), each independently is hydrogen,C₁₋₆alkyl, halo, C₁₋₆alkoxy, C₁₋₆alkyl-sulfonyl halo-C₁₋₆alkyl, orcyano.

In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa, IIIb,IIIc, IVa, IVb or IVc, R⁵ is

wherein R^(e) is as defined herein.

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, Ra,R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k),R^(m), R^(n), R^(o), R^(p), R^(q) or R^(r) is alkyl or contains an alkylmoiety, such alkyl is preferably lower alkyl, i.e. C₁-C₆alkyl, and morepreferably C₁-C₄alkyl.

The invention also provides methods for treating a disease mediated by aP2X₃ receptor antagonist, a P2X_(2/3) receptor antagonist, or both, themethod comprising administering to a subject in need thereof aneffective amount of a compound of any of formulas (I) through (VIII).The disease may be genitorurinary disease or urinary tract disease. Inother instances the disease may be a disease is associated with pain.The urinary tract disease may be: reduced bladder capacity; frequentmicturition; urge incontinence; stress incontinence; bladderhyperreactivity; benign prostatic hypertrophy; prostatitis; detrusorhyperreflexia; urinary frequency; nocturia; urinary urgency; overactivebladder; pelvic hypersensitivity; urethritis; prostatitis; pelvic painsyndrome; prostatodynia; cystitis; or idiophatic bladderhypersensitivity. The disease associated with pain may be: inflammatorypain; surgical pain; visceral pain; dental pain; premenstrual pain;central pain; pain due to burns; migraine or cluster headaches; nerveinjury; neuritis; neuralgias; poisoning; ischemic injury; interstitialcystitis; cancer pain; viral, parasitic or bacterial infection;post-traumatic injury; or pain associated with irritable bowel syndrome.The disease may be a respiratory disorder, such as chronic obstructivepulmonary disorder (COPD), asthma, or bronchospasm, or agastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS),Inflammatory Bowel Disease (IBD), biliary colic and other biliarydisorders, renal colic, diarrhea-dominant IBS, pain associated with GIdistension.

Representative compounds in accordance with the methods of the inventionare shown in Table 1.

TABLE 1 Mp or # Structure Name (Autonom ™) M + H 1

2′-Fluoro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 378 2

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-furan-2-yl-ethyl)-amide 161.9- 163.4° C. 3

4′-Chloro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 152.9- 155.0° C. 4

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid isopropylamide200.8- 202.0° C. 5

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin- 1-yl)-ethyl]-amide 106.5 110.7° C. 6

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)- amide 122.0- 125.0° C. 7

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1,1-dimethyl-2-morpholin-4-yl-ethyl)- amide 85.5- 87.0° C. 8

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide 352 9

5-Tetrazol-1-yl-biphenyl- 3-carboxylic acid (1- furan-2-yl-ethyl)-amide360 10

4′-Fluoro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 92.3- 93.2° C. 11

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-thiophen-2-yl-ethyl)-amide 143.2- 136.1° C. 12

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-butyl)-amide 128.3- 130.1° C. 13

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-phenyl-ethyl)-amide 114.1- 115.2° C. 14

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid cyclopropylamide320 15

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-ethyl-propyl)-amide 350 16

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide 338 17

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid tert-butylamide336 18

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid(1-furan- 2-yl-ethyl)-amide 392 19

3′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid(1-furan- 2-yl-ethyl)-amide 392 20

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid benzylamide 370 21

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-phenyl-ethyl)-amide 384 22

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-phenyl-ethyl)-amide 384 23

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-furan-2-yl-ethyl)-amide 428 24

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-naphthalen-2-yl- ethyl)-amide 434 25

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide 400 26

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide 400 27

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-methoxy-phenyl)-ethyl]-amide 414 28

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-methoxy-phenyl)-ethyl]-amide 414 29

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-chloro-phenyl)-ethyl]-amide 418 30

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-amide 402 31

4′-Ethyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 388 32

2′-Chloro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 394 33

2′-Ethoxy-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 404 34

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-pentyl)-amide 364 35

4′-Bromo-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide 417 36

4′-Bromo-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)- amide 439 37

4′-Ethyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide 366 38

2′,4′-Dimethyl-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 366 39

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 390 40

4′-Chloro-3′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 390 41

3′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 370 42

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 370 43

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 406 44

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 374 45

4′-Chloro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide 372 46

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-hydroxymethyl-2- methyl-propyl)-amide 366 47

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1,3-dimethyl-butyl)-amide 364 48

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid sec-butylamide 33649

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-cyclohexyl-ethyl)-amide 390 50

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-methyl-1-phenyl- ethyl)-amide 398 51

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (4-diethylamino-1-methyl-butyl)-amide 421 52

2-[(4′-Methyl-5-tetrazol- 1-yl-biphenyl-3- carbonyl)-amino]- propionicacid methyl ester 366 53

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid {1-[(pyridin-2-ylmethyl)-carbamoyl]- ethyl}-amide 442 54

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)- amide 407 55

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(2-dimethylamino-1- methyl-ethyl)-amide 365 56

4′-Chloro-2′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 386 57

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-chloro-phenyl)-1-methyl-ethyl]- amide 432 58

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-phenoxy-ethyl)-amide 414 59

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1,1-dimethyl-propyl)-amide 350 60

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(1-methyl-3-phenyl- propyl)-amide 412 61

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(2,6-dimethyl-phenoxy)-1-methyl- ethyl]-amide 442 62

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide 385 63

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-pyridin-4-yl-ethyl)-amide 385 64

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-pyridin-3-yl-ethyl)-amide 385 65

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-pyridin-2-yl-ethyl)-amide 439 66

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-pyridin-3-yl-ethyl)-amide 439 67

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-pyridin-4-yl-ethyl)-amide 439 68

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-pyridin-2-yl-ethyl)-amide 407 69

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-pyridin-3-yl-ethyl)-amide 407 70

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-pyridin-4-yl-ethyl)-amide 407 71

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methylcarbamoyl-ethyl)- amide 365 72

3-[(4′-Methyl-5-tetrazol- 1-yl-biphenyl-3- carbonyl)-amino]-butyric acidethyl ester 394 73

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide 338 74

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide 352 75

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide 352 76

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 370 77

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 425 78

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 445 79

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 390 80

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl- ethyl]-amide 484 81

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl- ethyl]-amide 502 82

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl- ethyl]-amide 522 83

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-acetyl-piperazin-1-yl)-1-methyl- ethyl]-amide 448 84

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-acetyl-piperazin-1-yl)-1- methyl-ethyl]-amide 466 85

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-acetyl-piperazin-1-yl)-1- methyl-ethyl]-amide 486 86

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 445 87

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (5-hydroxy-1,5-dimethyl-hexyl)-amide 408 88

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (5-hydroxy-1,5-dimethyl- hexyl)-amide 426 89

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (5-hydroxy-1,5-dimethyl- hexyl)-amide 446 90

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-(5-methyl-furan- 2-yl)-ethyl]-amide 388 91

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-(5-methyl-furan-2-yl)- ethyl]-amide 406 92

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-(5-methyl-furan-2-yl)- ethyl]-amide 426 93

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)- amide 407 94

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 390 95

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-2-yl-ethyl)-amide 403 96

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-3-yl-ethyl)-amide 403 97

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-4-yl-ethyl)-amide 403 98

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-2-yl-ethyl)-amide 423 99

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-3-yl-ethyl)-amide 423 100

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-4-yl-ethyl)-amide 423 101

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-methanesulfonyl-phenyl)- ethyl]-amide 462 102

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-(4-methanesulfonyl-phenyl)- ethyl]-amide 480 103

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-(4-methanesulfonyl-phenyl)- ethyl]-amide 500 104

2′,4'-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid [1-(4-methanesulfonyl-phenyl)- ethyl]-amide 484 105

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid [1-(4-methanesulfonyl-phenyl)- ethyl]-amide 516 106

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-methylsulfanyl-ethyl)- amide 368 107

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-methylsulfanyl- ethyl)-amide 386 108

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-methyl-2-methylsulfanyl- ethyl)-amide 390 109

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-methyl-2-methylsulfanyl- ethyl)-amide 422 110

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-methylsulfanyl- ethyl)-amide 406 111

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-methylsulfanyl- ethyl)-amide 406 112

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(2-fluoro-phenyl)-ethyl]-amide 402 113

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(3-fluoro-phenyl)-ethyl]-amide 402 114

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-2-yl-ethyl)-amide 423 115

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-3-yl-ethyl)-amide 423 116

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyridin-4-yl-ethyl)-amide 423 117

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-(4-methanesulfonyl-phenyl)- ethyl]-amide 500 118

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 445 119

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 390 120

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (2-methanesulfonyl-1- methyl-ethyl)-amide 450 121

2′-Chloro-4′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methanesulfonyl-1- methyl-ethyl)-amide 438 122

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-piperidin-1-yl-ethyl)- amide 405 123

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid(2-ethoxy-1-methyl- ethyl)-amide 366 124

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (3-methoxy-1-methyl-propyl)-amide 366 125

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (3-hydroxy-1-methyl-propyl)-amide 352 126

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 461 127

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 429 128

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid [1-(4-fluoro-phenyl)-ethyl]- amide 456 129

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-amide 402 130

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-thiomorpholin-4-yl- ethyl)-amide 423 131

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-methyl-2-(4-methyl-piperazin-1-yl)- ethyl]-amide 420 132

N-(1-Methyl-2- morpholin-4-yl-ethyl)-2- tetrazol-1-yl-6-p-tolyl-isonicotinamide 408 133

N-(2-Methoxy-1-methyl- ethyl)-3-(5-methyl- pyridin-2-yl)-5-tetrazol-1-yl-benzamide 353 134

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide 463 135

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1,5-dimethyl-hexyl)-amide 392 136

4′-Chloro-2′-fluoro-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl ethyl]-amide 522 137

2′,4′-Difluoro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl- ethyl]-amide 506 138

2′,4′-Dichloro-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl- ethyl]-amide 538 139

N-(1-Methyl-2- morpholin-4-yl-ethyl)-3- (5-methyl-pyridin-2-yl)-5-tetrazol-1-yl- benzamide 408 140

N-(2-Methoxy-1-methyl- ethyl)-3-(5-methyl- pyridin-2-yl)-5-tetrazol-1-yl-benzamide 353 141

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(3-hydroxy-piperidin-1-yl)-1-methyl- ethyl]-amide 421 142

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-3-morpholin-4-yl-propyl)- amide 421 143

N-[2-(4- Methanesulfonyl- piperazin-1-yl)-1-methyl- ethyl]-3-(5-methyl-pyridin-2-yl)-5-tetrazol- 1-yl-benzamide 485 144

3-(5-Fluoro-pyridin-2- yl)-N-[2-(4- methanesulfonyl-piperazin-1-yl)-1-methyl- ethyl]-5-tetrazol-1-yl- benzamide 489 145

3-(5-Fluoro-pyridin-2- yl)-N-(1-methyl-2- morpholin-4-yl-ethyl)-5-tetrazol-1-yl-benzamide 412 146

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-methyl-2-(3-oxo- piperazin-1-yl)-ethyl]- amide 420 147

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(3-methoxy-piperidin-1-yl)-1-methyl- ethyl]-amide 435 148

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-1-methyl- ethyl]-amide 435 149

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-1-methyl- ethyl]-amide 421 150

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-thiophen-3-yl-ethyl)-amide 390 151

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-thiophen-3-yl-ethyl)- amide 408 152

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 386 153

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 404 154

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-methyl-2-(1-oxo- 1lambda*4*- thiomorpholin-4-yl)- ethyl]-amide 439155

4-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(3-hydroxy-pyrrolidin-1-yl)-1- methyl-ethyl]-amide 407 156

6-Tetrazol-1-yl-4-p-tolyl- pyridine-2-carboxylic acid [2-(4-acetyl-piperazin-1-yl)-1-methyl- ethyl]-amide 449 157

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-pyrimidin-2-yl-ethyl)-amide 386 158

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(3-methoxy-piperidin-1-yl)- 1-methyl-ethyl]-amide 453 159

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-methoxy-piperidin-1-yl)- 1-methyl-ethyl]-amide 453 160

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-thiazol-2-yl-ethyl)-amide 391 161

2′-Fluoro-4-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-thiazol-2-yl-ethyl)-amide 409 163

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyrimidin-2-yl-ethyl)- amide 404 163

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 420 164

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 386 165

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 441 166

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-methanesulfonyl- piperazin-1-yl)-1-methyl ethyl]-amide 518 167

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-acetyl-piperazin-1-yl)-1- methyl-ethyl]-amide 482 168

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-pyridazin-4-yl-ethyl)-amide 386 169

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-3-oxo-3-piperidin-1-yl-propyl)- amide 433 170

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [3-(1,1-dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-3-oxo-propyl]- amide 483 171

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-isopropylcarbamoyl-1- methyl-ethyl)-amide 407 172

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-3-oxo-3-thiomorpholin-4-yl- propyl)-amide 451 173

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (2-cyclobutylcarbamoyl-1- methyl-ethyl)-amide 419 174

N-(1-Methyl-2- morpholin-4-yl-ethyl)-3 (4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol- 1-yl-benzamide 424 175

2′-Fluoro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)- amide 411 176

4′-Chloro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)- amide 427 177

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [(R)-2-(4-methanesulfonyl- piperidin-1-yl)-1-methyl- ethyl]-amide 483 178

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [(R)-2-(1,1-dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide 473179

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid[(R)-2-(4- methanesulfonyl- piperidin-1-yl)-1-methyl- ethyl]-amide 501180

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-thiazol-2-yl-ethyl)-amide 425 181

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [(R)-1-methyl-2-(3-oxo- piperazin-1-yl)-ethyl]- amide 454 182

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [(R)-1-methyl-2-(3-oxo- piperazin-1-yl)-ethyl]- amide 438 183

2′-Chloro-5-tetrazol-1-yl- biphenyl-3-carboxylic acid ((R)-1-methyl-2-morpholin-4-yl-ethyl)- amide 427 184

5-Tetrazol-1-yl-2′- trifluoromethyl-biphenyl- 3-carboxylic acid ((R)-1-methyl-2-morpholin-4-yl- ethyl)-amide 461 185

5-Tetrazol-1-yl-biphenyl- 3-carboxylic acid ((R)-1-methyl-2-morpholin-4-yl- ethyl)-amide 393 186

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [(R)-2-(4-fluoro-piperidin-1-yl)-1-methyl- ethyl]-amide 423 187

4′-Methyl-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 366 188

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 380 189

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((R)-1-methyl-2-morpholin-4-yl- ethyl)-amide 435 190

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 164.5- 166.2° C. 191

4°-Methyl-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 400 192

4′-Methyl-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((R)-1- methyl-2-morpholin-4-yl- ethyl)-amide 421 193

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[(R)-2-((S)-4-acetyl- 3-methyl-piperazin-1-yl)- 1-methyl-ethyl]-amide462 194

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [(R)-2-((S)-4-acetyl-3-methyl- piperazin-1-yl)-1-methyl- ethyl]-amide 480 195

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[(R)-2-(4-acetyl-3,5- dimethyl-piperazin-1-yl)- 1-methyl-ethyl]-amide476 196

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [(R)-2-(2,6-dimethyl-morpholin-4- yl)-1-methyl-ethyl]- amide 435 197

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [(R)-2-(1,1-dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide 489198

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid[(R)-2-(4- methanesulfonyl- piperidin-1-yl)-1-methyl- ethyl]-amide 517199

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid[(R)-2-(4- fluoro-piperidin-1-yl)-1- methyl-ethyl]-amide 457 200

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[(R)-2-(4,4-difluoro- piperidin-1-yl)-1-methyl- ethyl]-amide 441 201

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [(R)-2-(4,4-difluoro-piperidin-1- yl)-1-methyl-ethyl]- amide 475 202

4′-Difluoromethyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 443 203

5-(5-tert-Butyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1- methyl-2-morpholin-4-yl- ethyl)-amide 463 204

5-(5-tert-Butyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1- pyrazin-2-yl-ethyl)-amide 442 205

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-acetyl-3-methyl-piperazin-1-yl)-1- methyl-ethyl]-amide 462 206

2′-Fluoro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-acetyl-3-methyl- piperazin-1-yl)-1-methyl- ethyl]-amide 480 207

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 394 208

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 177.2- 178.0° C. 209

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-thiazol-2-yl-ethyl)-amide 433 210

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 449 211

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(3-fluoro-piperidin-1-yl)-1-methyl- ethyl]-amide 423 212

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid[2-(1,1- dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide497 213

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 366 214

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(3-fluoro-piperidin-1-yl)-1- methyl-ethyl]-amide 457 215

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-thiazol-2-yl-ethyl)-amide 419 216

5-(5-Isopropyl-tetrazol-1- yl)-4-methyl-biphenyl-3- carboxylic acid (1-thiazol-2-yl-ethyl)-amide 433 217

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 394 218

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-methyl-2-(8-oxa- 3-aza-bicyclo[3.2.1]oct- 3-yl)-ethyl]-amide 433 219

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 380 220

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-methyl-2-(8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- ethyl]-amide 467 221

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 85.5- 88.5° C. 222

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 449 223

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 174.6- 175.5° C. 224

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(4-hydroxy-4-methyl-piperidin-1-yl)-1- methyl-ethyl]-amide 435 225

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid[2-(1,1-dioxo- 1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide495 226

4′-Methyl-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid[2-(1,1- dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide469 227

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[2-(1,1- dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide483 228

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[2-(1,1- dioxo-1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide497 229

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid [2-(1,1- dioxo-1lambda*6*- thiomorpholin-4-yl)-1-methyl-ethyl]-amide 523 230

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (2- methoxy-1-methyl- ethyl)-amide 420 231

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (2- hydroxy-1-methyl-ethyl) amide 406 232

5-(5-Cyclopropyl- tetrazol-1-yl)-4-methyl- biphenyl-3-carboxylic acid(2-hydroxy-1- methyl-ethyl)-amide 378 233

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3 carboxylic acid (2-hydroxy-1-methyl-ethyl) amide 380 234

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 392 235

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-methyl-2-(3-oxa- 8-aza-bicyclo[3.2.1]oct- 8-yl)-ethyl]-amide 433 236

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(1-thiazol-2-yl- ethyl)-amide 431 237

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(1-pyrazin-2-yl- ethyl)-amide 426 238

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-pyridazin-4-yl-ethyl)- amide 414 239

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3 carboxylic acid [1-methyl-2-(3-oxa-8-aza- bicyclo[3.2.1]oct-8-yl)- ethyl]-amide 467 240

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (1- thiazol-2-yl-ethyl)-amide 458 241

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-methyl-2-(2-oxa- 5-aza-bicyclo[2.2.1]hept- 5-yl)-ethyl]-amide 419 242

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (1- pyrazin-2-yl-ethyl)-amide 454 243

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 380 244

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-hydroxy-1- methyl-ethyl)-amide 378 245

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-methyl-2-(2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl)- ethyl]-amide 453 246

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (2- hydroxy-1-methyl-ethyl)- amide 406 247

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (1- methyl-2-morpholin-4-yl- ethyl)-amide 475 248

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(1-methyl-2- morpholin-4-yl-ethyl)- amide 447 249

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[1-methyl-2-(2-oxa- 8-aza-spiro[4.5]dec-8- yl)-ethyl]-amide 461 250

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [1-methyl-2-(2-oxa-8-aza- spiro[4.5]dec-8-yl)- ethyl]-amide 495 251

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 396 252

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 410 253

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-hydroxy-1- methyl-ethyl)-amide 396 254

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-hydroxy-1- methyl-ethyl)-amide 382 255

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-hydroxy-1- methyl-ethyl)-amide 382 256

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-hydroxy-1- methyl-ethyl)-amide 396 257

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3 -carboxylic acid(1-thiazol-2-yl- ethyl)-amide 449 258

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(1-thiazol-2-yl- ethyl)-amide 435 259

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl biphenyl-3-carboxylic acid(1-pyrazin-2-yl- ethyl)-amide 430 260

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(1-pyrazin-2-yl- ethyl)-amide 444 261

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(1-methyl-2- morpholin-4-yl-ethyl)- amide 465 262

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl biphenyl-3-carboxylic acid(1-methyl-2- morpholin-4-yl-ethyl)- amide 451 263

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid[2-(1,1-dioxo- 1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide499 264

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid[2-(1,1-dioxo- 1lambda*6*- thiomorpholin-4-yl)-1- methyl-ethyl]-amide513 265

2′-Chloro-4′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 438 266

2′-Chloro-4′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 390 267

2′-Chloro-4′-fluoro-5-(5- tnethyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 404 267

2′-Chloro-4′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-thiazol-2-yl- ethyl)-amide 443 269

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4-fluoro- biphenyl-3-carboxylicacid (1-thiazol-2-yl- ethyl)-amide 457 270

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-fluoro- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 404 271

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-fluoro- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 404 272

2′-Chloro-4′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 390 273

2′-Chloro-4′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid [2-(1,1-dioxo- 1lambda*6*- thiomorpholin-4-yl)-1-methyl-ethyl]-amide 507 274

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-fluoro- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 418 275

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-fluoro- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 418 276

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-fluoro- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 452 277

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-fluoro- biphenyl-3-carboxylicacid [2-(1,1-dioxo- 1lambda*6*- thiomorpholin-4-yl)-1-methyl-ethyl]-amide 521 278

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid [2-(3-fluoro-4-methoxy-piperidin-1-yl)- 1-methyl-ethyl]-amide 453 279

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(3-fluoro-4-methoxy- piperidin-1-yl)-l-methyl- ethyl]-amide 487 280

4′-Methyl-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 366 281

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 380 282

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 394 283

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 394 284

5-(5-Cyclopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 392 285

5-(5-Methoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 396 286

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 410 287

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (2- methoxy-1-methyl- ethyl)-amide 420 288

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 432 289

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 418 290

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 418 291

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 432 292

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 466 293

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-thiazol-2-yl- ethyl)-amide 471 294

2′-Chloro-4′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid [2-(1,1-dioxo- 1lambda*6*- thiomorpholin-4-yl)-1-methyl-ethyl]-amide 535 295

2′-Chloro-4′-methyl-5- tetrazol-1-yl-biphenyl-3- carboxylic acid [2-(4-acetyl-3-methyl- piperazin-1-yl)-1-methyl- ethyl]-amide 497 296

4′-Chloro-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 386 297

4′-Chloro-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 372 298

4′-Chloro-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 372 299

4′-Chloro-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 420 300

4′-Chloro-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 441 301

5-(5-Ethyl-tetrazol-1-yl)- 6,4′-dimethyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 394 302

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 414 303

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 400 304

5-(5-Ethyl-tetrazol-1-yl)- 6,4′-dimethyl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 448 305

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 400 306

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 469 307

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 448 308

4-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid[2-(4- acetyl-piperazin-1-yl)-1- methyl-ethyl]-amide 510 309

5-(5-Isopropyl-tetrazol-1- yl)-6,4′-dimethyl- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 408 310

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 455 311

5-(5-Isopropyl-tetrazol-1- yl)-6,4′-dimethyl- biphenyl-3-carboxylic acid(1-methyl-2- morpholin-4-yl-ethyl)- amide 463 312

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 434 313

6,4′-Dimethyl-5-tetrazol- 1-yl-biphenyl-3- carboxylic acid (1-methyl-2-morpholin-4-yl- ethyl)-amide 421 314

N-((R)-1-Methyl-2- morpholin-4-yl-ethyl)-3- (3-methyl-thiophen-2-yl)-5-tetrazol-1-yl- benzamide 413 315

N-((R)-1-Methyl-2- morpholin-4-yl-ethyl)-3- (5-methyl-thiophen-2-yl)5-tetrazol-1-yl- benzamide 413 316

3-(5-Chloro-thiophen-2- yl)-N-((R)-1-methyl-2- morpholin-4-yl-ethyl)-5-tetrazol-1-yl-benzamide 433 317

5-(1-Ethyl-1H-tetrazol-5- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 380 318

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(5-amino- pyrazin-2-ylmethyl)- amide 429 319

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(3-amino pyrazin-2-ylmethyl)- amide 429 320

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-1-pyrazin-2-yl- ethyl)-amide 79.5- 81.9°C. 321

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-pyridin-2-yl- cyclopropyl)-amide 110.0- 114.0° C. 322

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-hydroxymethyl- cyclopropyl)-amide 392 323

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-methyl-1H-pyrazol-3- ylmethyl)-amide 416 324

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (3-chloro-pyrazin-2- ylmethyl)-amide 198.5- 200.5° C. 325

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(2- amino-pyrimidin-5-yl)- ethyl]-amide 184.0- 185.0° C. 326

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-methyl-1H-imidazol-4- ylmethyl)-amide 218.0- 220.3° C. 327

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(6-amino-pyridin-3-yl)- ethyl]-amide 428 328

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(6-amino-pyrazin-2-yl)- ethyl]-amide 429 329

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(2-amino-pyridin-4-yl)- ethyl]-amide 428 330

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(2- dimethylamino- pyrimidin-5-yl)-ethyl]- amide 471 331

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(6-amino- pyridin-2-ylmethyl)- amide 428 332

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-oxo-1,2-dihydro- pyrimidin-4-yl)-amide 416333

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acidpiperidin- 3-ylamide 405 334

5-[5-(1-Ethoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid ((R)-2-methoxy-1- methyl-ethyl)-amide 424 335

5-[5-(1-Ethoxy-ethyl)- tetrazol-yl]-4′-methyl- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 410 336

5-[5-(1-Ethoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 474 337

5-[5-(1-Ethoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (5-methyl-pyrazin-2- ylmethyl)-amide 474 338

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-methylamino-pyridin-4- ylmethyl)-amide 444 339

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-dimethylamino-pyridin- 4-ylmethyl)-amide 458 340

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((S)-2- hydroxy-1-methyl- propyl)-amide 380 341

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (5- methyl-pyrazin-2- ylmethyl)-amide 470 342

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(2-dimethylamino-pyridin- 4-yl)-ethyl]-amide 472 343

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(2-methylamino-pyridin-4- yl)-ethyl]-amide 458 344

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 429 345

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrimidin-5- yl-ethyl)-benzamide 429 346

3-(5-Isopropyl-tetrazol-1- yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 165.0- 168.0° C. 347

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-pyrimidin-5-yl-ethyl)- amide 428 348

5-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (1-pyrimidin-5-yl- ethyl)-amide 444 349

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(2- methyl-pyridin-4-yl)- ethyl]-amide 441 350

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(2-oxo- 1,2-dihydro-pyrimidin-4- yl)-amide 416 351

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-oxo-1,2-dihydropyrimidin-4- yl)-amide 402 352

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (5-methyl-2-oxo-1,2- dihydro-pyrimidin-4-yl)- amide 430 353

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (6-methylamino-pyridin-3- ylmethyl)-amide 428 354

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (6-dimethylamino-pyridin- 3-ylmethyl)-amide 442 355

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid (1- pyrimidin-5-yl-ethyl)- amide 454 356

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(S)-1-(6- methylamino-pyrimidin- 4-yl)-ethyl]-amide 108.0- 109.4° C.357

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(6-dimethylamino-pyridin- 3-yl)-ethyl]-amide 456 358

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(6-methylamino-pyridin-3- yl)-ethyl]-amide 442 359

5-[5-((R)-2-Methoxy-1- methyl-ethyl)-tetrazol-l-yl]-4′-methyl-biphenyl-3- carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)- amide 410 360

5-[5-((R)-2-Methoxy-1- methyl-ethyl)-tetrazol-1-yl]-4′-methyl-biphenyl-3- carboxylic acid (1- pyrazin-2-yl-ethyl)-amide458 361

5-[5-((R)-2-Methoxy-1- methyl-ethyl)-tetrazol-1-yl]-4′-methyl-biphenyl-3- carboxylic acid (5- methyl-pyrazin-2-ylmethyl)-amide 458 362

5-[5-((S)-1-Methoxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 396 363

5-[5-((S)-1-Methoxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (1- pyrazin-2-yl-ethyl)-amide 444 364

5-[5-((S)-1-Methoxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (5- methyl-pyrazin-2- ylmethyl)-amide 444 365

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(2- methylamino-pyrimidin- 5-yl)-ethyl]-amide 154.0- 155.0° C. 366

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-methyl-2-oxo-1,2- dihydro-pyrimidin-4-yl)- amide 430 367

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(6- methyl-pyridin-3-yl)- ethyl]-amide 441 368

5-[5-((R)-1-Methoxy- ethyl)-tetrazol-1-yl]-4- methyl-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 396 369

5-[5-((R)-1-Methoxy- ethyl)-tetrazol-1-yl]-4- methyl-biphenyl-3-carboxylic acid (5- methyl-pyrazin-2- ylmethyl)-amide 444 370

5-[5-((S)-1-Methoxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (1- pyrimidin-5-yl-ethyl)- amide 444 371

5-[5-((R)-1-Methoxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (1- pyrimidin-5-yl-ethyl)- amide 444 372

5-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (1-pyrimidin-5-yl- ethyl)-amide 444 373

2′-Fluoro-5-[5-(1- hydroxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 400 374

2′-Fluoro-5-[5-(1- hydroxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid (1- pyrazin-2-yl-ethyl)-amide 448 375

2′-Fluoro-5-[5-(1- hydroxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid (1- pyrimidin-5-yl-ethyl)- amide 448 376

2′-Fluoro-5-[5-(1- hydroxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid (5- methyl-pyrazin-2- ylmethyl)-amide 448 377

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acidoxetan-3- ylamide 378 378

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid oxetan-3-ylamide 396 379

2′-Fluoro-5-[5-(1- methoxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 414 380

2′-Fluoro-5-[5-(1- methoxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid (1- pyrazin-2-yl-ethyl)-amide 462 381

2′-Fluoro-5-[5-(1- methoxy-ethyl)-tetrazol- 1-yl]-4′-methyl-biphenyl-3-carboxylic acid (5- methyl-pyrazin-2- ylmethyl)-amide 462 382

5-[5-(1-Dimethylamino- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 409 383

5-[5-(1-Dimethylamino- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (1- pyrazin-2-yl-ethyl)-amide 457 384

5-[5-(1-Dimethylamino- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (5- methyl-pyrazin-2- ylmethyl)-amide 457 385

5-[5-((S)-1-Hydroxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 382 386

5-[5-((S)-1-Hydroxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (1- pyrazin-2-yl-ethyl)-amide 430 387

5-[5-((S)-1-Hydroxy- ethyl)-tetrazol-1-yl]-4′- methyl-biphenyl-3-carboxylic acid (5- methyl-pyrazin-2- ylmethyl)-amide 430 388

5-(5- Dimethylaminomethyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1- methyl-ethyl)-amide 395 389

5-(5- Dimethylaminomethyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 443 390

5-(5- Dimethylaminomethyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 443 391

5-[5-(1-Hydroxy-ethyl)- tetrazol-1-yl]-4-methyl- biphenyl-3-carboxylicacid ((S)-1-pyrazin-2-yl- ethyl)-amide 90.0- 92.0° C. 392

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid [1-(6-methyl- pyridin-3-yl)-ethyl]- amide 459393

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid [1-(6-chloro-5- methyl-pyridin-2-yl)-ethyl]-amide 493 394

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(4- methyl-thiazol-2-yl)- ethyl]-amide 447 396

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2,6-dimethyl-pyridin-3- ylmethyl)-amide 441 396

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[1-(2,6- dimethyl-pyridin-3-yl)- ethyl]-amide 441 397

N-Cyclopropyl-3-(5- isopropyl-tetrazol-1-yl) 5-(5-methyl-pyridin-2-yl)-benzamide 363 398

3-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-5-(5- methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 445 399

3-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-N-(5- methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 445 400

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-[5-(1- methoxy-ethyl)-tetrazol-1-yl]-5-(5-methyl- pyridin-2-yl)-benzamide 397 401

N-Cyclopropyl-3-[5-(1- methoxy-ethyl)-tetrazol- 1-yl]-5-(5-methyl-pyridin-2-yl)-benzamide 379 402

3-(5-Chloro-pyridin-2- yl)-5-(5-ethyl-tetrazol-1- yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide 70.9- 73.3° C. 403

3-(5-Chloro-pyridin-2- yl)-5-(5-ethyl-tetrazol-1-yl)-N-(5-methyl-pyrazin- 2-ylmethyl)-benzamide 170.1- 172.4° C. 404

3-(5-Chloro-pyridin-2- yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 449 405

3-(5-Ethyl-tetrazol-1-yl)- N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide 168.0- 171.1° C. (HCl salt) 406

3-(5-Chloro-pyridin-2- yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 179.5- 181.2° C. 407

3-(5-Ethyl-tetrazol-1-yl)- 5-(5-methyl-pyridin-2- yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide 168.0- 169.3° C. 408

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(2H- pyrazol-3-ylmethyl)- amide 402 409

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(thiazol- 2-ylmethyl)-amide 419 410

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1H- imidazol-2-ylmethyl)- amide 402 411

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(imidazo[1,2-α]pyridin-2- ylmethyl)-amide 452 412

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (6-methyl-pyridin-2- ylmethyl)-amide 427 413

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1-ethyl- 1H-pyrazol-3-ylmethyl)- amide 430 414

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (3-methyl-pyridin-2- ylmethyl)-amide 427 415

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (4-methyl-thiazol-5- ylmethyl)-amide 433 416

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1-ethyl- 1H-imidazol-2- ylmethyl)-amide 430 417

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1-ethyl- 1H-imidazol-2- ylmethyl)-amide 430 418

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-methyl-1H-pyrazol-4- ylmethyl)-amide 416 419

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(3H- imidazo[4,5-b]pyridin-2- ylmethyl)-amide 453 420

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(3,5- difluoro-pyridin-2- ylmethyl)-amide 449 421

3-(3,5-Dimethyl-pyridin- 2-yl)-5-(5-ethyl-tetrazol- 1-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 429 422

3-(3,5-Dimethyl-pyridin- 2-yl)-5-(5-ethyl-tetrazol- 1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)- benzamide 429 423

3-(3,5-Dimethyl-pyridin- 2-yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 443 424

3-(3,5-Dimethyl-pyridin- 2-yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 443 425

3-(3,5-Dimethyl-pyridin- 2-yl)-N-((S)-2-hydroxy- 1-methyl-ethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 395 426

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- isobutyl-tetrazol-1-yl)-5-(5-methyl-pyridin-2-yl)- benzamide 395 427

3-(5-Isobutyl-tetrazol-1- yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 443 428

3-(5-Isobutyl-tetrazol-1- yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 443 429

N-Cyclopropyl-3-(5- isobutyl-tetrazol-1-yl)-5- (5-methyl-pyridin-2-yl)-benzamide 377 430

3-(5-Isobutyl-tetrazol-1- yl)-N-((R)-2-methoxy-1- methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 409 431

3-(3-Chloro-5-methyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 125.4- 128.3° C. (HCl salt)432

3-(3-Chloro-5-methyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 185.4- 186.3° C. (HCl salt) 433

3-(3-Chloro-5-methyl- pyridin-2-yl)-N-((S)-2- hydroxy-1-methyl-ethyl)-5-(5-isopropyl-tetrazol-1- yl)-benzamide 110.0- 112.0° C. 434

3-(3-Fluoro-5-methyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 447 435

3-(3-Fluoro-5-methyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 447 436

3-(3-Fluoro-5-methyl- pyridin-2-yl)-N-((S)-2- hydroxy-1-methyl-ethyl)-5-(5-isopropyl-tetrazol-1- yl)-benzamide 399 437

3-(5-Ethyl-tetrazol-1-yl)- 5-(3-fluoro-5-methyl- pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 433 438

3-(5-Ethyl-tetrazol-1-yl)- 5-(3-fluoro-5-methyl- pyridin-2-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 433 439

3-(5-Ethyl-tetrazol-1-yl)- 5-(3-fluoro-5-methyl- pyridin-2-yl)-N-((S)-2-hydroxy-1-methyl-ethyl)- benzamide 385 440

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl- pyridin-2-yl)-5-(5-trifluoromethyl-tetrazol- 1-yl)-benzamide 167.0- 170.0° C. (HCl salt)441

3-(5-Methyl-pyridin-2- yl)-N-(1-pyrazin-2-yl- ethyl)-5-(5-trifluoromethyl-tetrazol 1-yl)-benzamide 144.0- 146.0° C. (HCl salt) 442

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- methyl-pyridin-2-yl)-5-(5-trifluoromethyl- tetrazol-1-yl)-benzamide 184.3- 185.1° C. (HCl salt)443

N-Cyclopropyl-3-(5- methyl-pyridin-2-yl)-5- (5-trifluoromethyl-tetrazol-1-yl)-benzamide 204.2- 205.1° C. (HCl salt) 444

3-(5-Chloro-pyridin-2- yl)-N-(3,5-difluoro- pyridin-2-ylmethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 80.0- 82.0° C. 445

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(6-fluoro- pyridin-2-ylmethyl)- amide 80.0- 81.0° C. 446

3-(5-Chloro-pyridin-2- yl)-N-(6-fluoro-pyridin- 2-ylmethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 80.0- 81.0° C. 447

3-(5-Chloro-pyridin-2- yl)-N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 124.0- 125.0° C. 448

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl- pyridin-2-yl)-5-(5-pentafluoroethyl-tetrazol- 1-yl)-benzamide 132.0- 133.0° C. (HCl salt)449

3-(5-Methyl-pyridin-2- yl)-5-(5-pentafluoroethyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 134.0- 135.0° C. (HCl salt) 450

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- methyl-pyridin-2-yl)-5-(5-pentafluoroethyl- tetrazol-1-yl)-benzamide 193.0- 193.5° C. (HClsalt) 451

N-Cyclopropyl-3-(5- methyl-pyridin-2-yl)-5- (5-pentafluoroethyl-tetrazol-1-yl)-benzamide 182.0- 183.0° C. (HCl salt) 452

3-[5-(1,1-Difluoro-ethyl)- tetrazol-1-yl]-N-(5- methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 188.0- 190.0° C. (HClsalt) 453

3-[5-(1,1-Difluoro-ethyl)- tetrazol-1-yl]-5-(5- methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 187.5- 188.0° C. (HCl salt) 454

3-[5-(1,1-Difluoro-ethyl)- tetrazol-1-yl]-N-((S)-2-hydroxy-1-methyl-ethyl)- 5-(5-methyl-pyridin-2- yl)-benzamide 207.5-208.5° C. (HCl salt) 455

N-Cyclopropyl-3-[5-(1,1- difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin- 2-yl)-benzamide 190.4- 192.0° C. (HCl salt) 456

3-(5-Chloro-pyridin-2- yl)-N-cyclopropyl-5-(5- isopropyl-tetrazol-1-yl)-benzamide 107.0- 108.0° C. (HCl salt) 457

3-(5-Chloro-pyridin-2- yl)-N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-trifluoromethyl-tetrazol- 1-yl)-benzamide 172.0- 173.0° C. (HCl salt)458

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin-1-yl)-N-((S-1-pyrazin-2- yl-ethyl)-benzamide 165.0- 165.6° C. (HCl salt)459

3-(5-Chloro-pyridin-2- yl)-N-cyclopropyl-5-(5- trifluoromethyl-tetrazol-1-yl)-benzamide 221.3- 223.0° C. (HCl salt) 460

3-(3-Fluoro-5-methyl- pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-5-(5-trifluoromethyl-tetrazol- 1-yl)-benzamide 473 461

3-(3-Fluoro-5-methyl- pyridin-2-yl)-N-(5- methyl-pyrazin-2-ylmethyl)-5-(5- trifluoromethyl-tetrazol- 1-yl)-benzamide 476 462

3-(3-Fluoro-5-methyl- pyridin-2-yl)-N-((S)-2- hydroxy-1-methyl-ethyl)5-(5-trifluoromethyl- tetrazol-1-yl)-benzamide 425 463

N-Cyclopropyl-3-(3- fluoro-5-methyl-pyridin- 2-yl)-5-(5-trifluoromethyl-tetrazol- 1-yl)-benzamide 407 464

3-(5-Chloro-pyridin-2- yl)-N-(5-methyl-pyrazin 2-ylmethyl)-5-(5-trifluoromethyl-tetrazol- 1-yl)-benzamide 166.0- 168.0° C. (HCl salt)465

3-(5-Chloro-pyridin-2- yl)-5-(5-isobutyl-tetrazol- 1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)- benzamide 109.0- 110.0° C. (HCl salt) 466

3-(5-Chloro-pyridin-2- yl)-AN-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-isobutyl-tetrazol-1-yl)- benzamide 94.5- 96.0° C. (HCl salt) 467

N-(3,5-Difluoro-pyridin- 2-ylmethyl)-3-(5- isopropyl-tetrazol-1-yl)-5-(5-methyl-pyridin-2- yl)-benzamide 450 468

N-(1,5-Dimethyl-1H- pyrazol-3-ylmethyl)-3-(5- isopropyl-tetrazol-1-yl)-5-(5-methyl-pyridin-2- yl)-benzamide 152.0- 153.0° C. (HCl salt) 469

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin-2-yl)-N-[1-(5-methyl- pyridin-2-yl)-ethyl]- benzamide 153.0- 155.0° C.(HCl salt) 470

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin-2-yl)-N-[1-(6-methyl- pyridin-2-yl)-ethyl]- benzamide 161.5- 162.0° C.(HCl salt) 471

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin- 2-yl)-N-(6-trifluoromethyl-pyridin- 3-ylmethyl)-benzamide 149.0- 151.0° C. (HClsalt) 472

3-(5-Butyl-tetrazol-1-yl)- N-((R)-2-methoxy-1- methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 409 473

3-(5-Butyl-tetrazol-1-yl)- N-cyclopropyl-5-(5- methyl-pyridin-2-yl)-benzamide 377 474

3-(5-Butyl-tetrazol-1-yl)- N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide \395 475

3-(5-Butyl-tetrazol-1-yl)- 5-(5-methyl-pyridin-2- yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide 443 476

3-(5-Butyl-tetrazol-1-yl)- N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide 443 477

3-(3,5-Difluoro-pyridin- 2-yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 451 478

3-(3,5-Difluoro-pyridin- 2-yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 451 479

3-(5-Fluoromethyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 135.6- 137.5° C. (HCl salt)480

3-(3,5-Difluoro-pyridin- 2-yl)-N-((S)-2-hydroxy- 1-methyl-ethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 403 481

N-Cyclopropyl-3-(3,5- difluoro-pyridin-2-yl)-5- (5-isopropyl-tetrazol-1-yl)-benzamide 385 482

N-[(S)-1-(5-Methyl- pyrazin-2-yl)-ethyl]-3-(5- methyl-pyridin-2-yl)-5-(5-trifluoromethyl- tetrazol-1-yl)-benzamide 455 483

3-(5-Fluoro-pyridin- yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 88.0- 89.0 5° C. (HCl salt) 484

3-(5-Fluoro-pyridin-2- yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 149.0- 150.0° C. (HCl salt) 485

3-(5-Chloro-pyridin-2- yl)-N-cyclopropyl-5-(5 isobutyl-tetrazol-1-yl)-benzamide 104.0- 105.0° C. (HCl salt) 486

3-(5-Chloro-pyridin-2- yl)-N-isopropyl-5-(5- trifluoromethyl-tetrazol-1-yl)-benzamide 216.5- 217.7° C. (HCl salt) 487

3-(5-Chloro-pyridin-2- yl)-5-(5-isobutyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 114.0- 115.0° C. (HCl salt)488

3-(5-Fluoro-pyridin-2- yl)-N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 104.5- 105.0° C. (HCl salt) 489

N-Cyclopropyl-3-(5- fluoro-pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-benzamide 94.0- 95.0° C. (HCl salt) 490

3-(3,5-Difluoro-pyridin 2-yl)-5-(5-isobutyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 465 491

3-(3,5-Difluoro-pyridin- 2-yl)-5-(5-isobutyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 465 492

3-(3,5-Difluoro-pyridin- 2-yl)-N-((S)-2-hydroxy- 1-methyl-ethyl)-5-(5-isobutyl-tetrazol-1-yl)- benzamide 417 493

N-Cyclopropyl-3-(3,5- difluoro-pyridin-2-yl)-5-(5-isobutyl-tetrazol-1-yl)- benzamide 399 494

3-(5-Methyl-pyridin-2- yl)-N-[2-(3-oxo- piperazin-1-yl)-ethyl]-5-(5-trifluoromethyl- tetrazol-1-yl)-benzamide 178.0- 179.0° C. 495

3-(5-tert-Butyl-tetrazol- 1-yl)-N-((R)-2-methoxy- 1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 409 496

3-(5-tert-Butyl-tetrazol- 1-yl)-N-cyclopropyl-5-(5-methyl-pyridin-2-yl)- benzamide 377 497

3-(5-tert-Butyl-tetrazol- 1-yl)-N-((S)-2-hydroxy- 1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 395 498

3-(5-tert-Butyl-tetrazol- 1-yl)-5-(5-methyl- pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 443 499

3-(5-tert-Butyl-tetrazol- 1-yl)-N-(5-methyl- pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 443 500

3-(5-Methyl-pyridin-2- yl)-5-(5-propyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 114.0- 115.0° C. (HCl salt)501

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl- pyridin-2-yl)-5-(5-propyl-tetrazol-1-yl)- benzamide 148.0- 149.0° C. (HCl salt) 502

N-Cyclopropyl-3-(5- methyl-pyridin-2-yl)-5- (5-propyl-tetrazol-1-yl)benzamide 120.0- 121.0° C. (HCl salt) 503

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- methyl-pyridin-2-yl)-5-(5-propyl-tetrazol-1-yl)- benzamide 121.0- 122.0° C. (HCl salt) 504

3-(5-Chloro-pyridin-2- yl)-5-(5-propyl-tetrazol 1-yl)-N-(1-pyrazin-2-ylethyl)-benzamide 85.0- 86.0° C. (HCl salt) 505

3-(5-Chloro-pyridin-2- yl)-N-(5-methyl-pyrazin- 2-ylmethyl)-5-(5-propyl-tetrazol-1-yl)-benzamide 90.0- 91.0° C. (HCl salt) 506

3-(5-Chloro-pyridin-2- yl)-N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-propyl-tetrazol-1-yl)- benzamide 507

N-Cyclopropyl-3-(5- cyclopropylmethyl- tetrazol-1-yl)-5-(5-methyl-pyridin-2-yl)- benzamide 375 508

3-(5-Cyclopropylmethyl- tetrazol-1-yl)-N-((S)-2-hydroxy-1-methyl-ethyl)- 5-(5-methyl-pyridin-2- yl)-benzamide 393 509

3-(5-Cyclopropylmethyl- tetrazol-1-yl)-5-(5- methyl-pyridin-2-yl)-Ar-(1-pyrazin-2-yl-ethyl)- benzamide 441 510

3-(5-Cyclopropylmethyl- tetrazol-1-yl)-N-(5- methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 441 511

3-(5-Difluoromethyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 465 512

3-(5-Difluoromethyl- pyridin-2-yl)-5-(5- isopropyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 465 513

3-(5-Methyl-pyridin-2- yl)-5-(5-methyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 144.5- 146.0° C. (HCl salt)514

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl- pyridin-2-yl)-5-(5-methyl-tetrazol-1-yl)- benzamide 158.0- 160.0° C. (HCl salt) 515

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- methyl-pyridin-2-yl)-5-(5-methyl-tetrazol-1-yl)- benzamide 192.3- 193.4° C. (HCl salt) 516

3-(5-Cyclopropylmethyl- tetrazol-1-yl)-N-(2- dimethylamino-1-methyl-ethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 406 517

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-dimethylamino-1-methyl- ethyl)-amide 393 518

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl- pyrimidin-2-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 430 519

3-(5-Isopropyl-tetrazol-1- yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyrimidin-2-yl)- benzamide 430 520

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- isopropyl-tetrazol-1-yl)-5-(5-methyl-pyrimidin-2- yl)-benzamide 382 521

N-Cyclopropyl-3-(5- isopropyl-tetrazol-1-yl)- 5-(5-methyl-pyrimidin-2-yl)-benzamide 364 522

3-(5-Fluoro-pyridin-2- yl)-5-(5-isobutyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 84.0- 86.0° C. (HCl salt) 523

3-(5-Fluoro-pyridin-2- yl)-5-(5-isobutyl-tetrazol- 1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)- benzamide 80.0- 83.0° C. (HCl salt) 524

N-Cyclopropyl-3-(5- fluoro-pyridin-2-yl)-5-(5- isobutyl-tetrazol-1-yl)-benzamide 78.0- 80.0° C. (HCl salt) 525

3-[5-(1,1-Difluoro-ethyl)- tetrazol-1-yl]-5-(5- methyl-pyridin-2-yl)-N-((S)-1-pyrazin-2-yl- ethyl)-benzamide 85.0- 86.0° C. 526

3-(5-Isopropyl-tetrazol-1- yl)-N-(5-methyl- isoxazol-3-ylmethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 418 527

3-(5-Isopropyl-tetrazol-1- yl)-N-(5-methy-1H- imidazol-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 417 528

3-(5-Isopropyl-tetrazol-1- yl)-N-(6-methyl-pyridin- 3-yl)-5-(5-methyl-pyridin-2-yl)-benzamide 414 529

3-(5-Isopropyl-tetrazol-1- yl)-5-(5-methyl-pyridin- 2-yl)-N-(4H-[1,2,4]triazol-3- ylmethyl)-benzamide 404 530

3-(5-Isopropyl-tetrazol-1- yl)-N-(5-methoxy-1H- benzoimidazol-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 483 531

3-(5-Chloro-pyridin-2- yl)-5-(5-ethyl-tetrazol-1- yl)-N-(2-hydroxy-1-methyl-ethyl)-benzamide 89.0- 90.0° C. (HCl salt) 532

3-(5-Chloro-pyridin-2- yl)-5-(5-cyclopropyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 447 533

3-(5-Chloro-pyridin-2- yl)-5-(5-cyclopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 447 534

3-(5-Chloro-pyridin-2- yl)-5-(5-cyclopropyl- tetrazol-1-yl)-N-(2-hydroxy-1-methyl-ethyl)- benzamide 399 535

3-(5-Chloro-pyridin-2- yl)-N-cyclopropyl-5-(5- cyclopropyl-tetrazol-1-yl)-benzamide 381 536

3-(5-Cyclopropyl- tetrazol-1-yl)-5-(5- methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 427 537

3-(5-Cyclopropyl- tetrazol-1-yl)-N-(5- methyl-pyrazin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 427 538

3-(5-Cyclopropyl- tetrazol-1-yl)-N-(2- hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2- yl)-benzamide 379 539

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acidpyridazin-4-ylamide 386 540

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(6-amino- pyridin-2-yl)-amide 115.7- 118.5° C. 541

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(2-amino- pyrimidin-4-yl)-amide 415 542

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(2-amino- pyridin-4-yl)-amide 249.7- 251.0° C. 543

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(2-amino- pyridin-4-yl)-amide 414 544

2′-Chloro-4′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1- methyl-ethyl)-amide 418 545

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 416 546

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid ((S)-2- methoxy-1-methyl- ethyl)-amide 430 547

2′-Chloro-4′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid ((S)-2-methoxy-1- methyl-ethyl)-amide 431 548

2′-Chloro-4′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid [(R)-2-(1,1-dioxo- 1λ⁶-thiomorpholin-4-yl)-1-methyl-ethyl]-amide 535 549

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid [(R)-2- (1,1-dioxo-1λ⁶- thiomorpholin-4-yl)-1-methyl-ethyl]-amide 533 550

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid (1- pyrazin-2-yl-ethyl)-amide 478 551

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid (1- thiazol-2-yl-ethyl)-amide 483 552

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid (2- hydroxy-1-methyl-ethyl)- amide 416 553

2′-Chloro-5-(5- cyclopropyl-tetrazol-1- yl)-4′-fluoro-biphenyl-3-carboxylic acid (2- methoxy-1-methyl- ethyl)-amide 430 554

2′-Chloro-4′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (2-hydroxy-1- methyl-ethyl)-amide 418 555

2′-Chloro-4′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 480 556

2′-Chloro-4′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (1-thiazol-2-yl- ethyl)-amide 485 557

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-methoxy-1- methyl-ethyl)-amide 446 558

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 432 559

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 432 560

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 446 561

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 494 562

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-thiazol-2-yl- ethyl)-amide 499 563

2′-Chloro-4′-fluoro-5-(5- isobutyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid [(R)-2-(1,1-dioxo- 1λ⁶-thiomorpholin-4-yl)- 1-methyl-ethyl]-amide549 564

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(R)-2- (1,1-dioxo-1λ⁶- thiomorpholin-4-yl)-1- methyl-ethyl]-amide 511565

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((S)-2- methoxy-1-methyl- ethyl)-amide 408 566

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((S)-2- hydroxy-1-methyl-ethyl)- amide 394 567

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 394 568

5-(5-Isobutyl-tetrazol-l- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 408 569

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-thiazol-2-yl-ethyl)-amide 461 570

2′-Chloro-4′-fluoro-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3-carboxylic acid (2- hydroxy-1-methyl-ethyl)- amide 444 571

2′-Chloro-4′-fluoro-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3-carboxylic acid ((S)-2- hydroxy-1-methyl-ethyl)- amide 444 572

2′-Fluoro-4′-methyl-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 418 573

2′-Fluoro-4′-methyl-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-thiazol-2-yl- ethyl)-amide 423 574

2′-Fluoro-4′-methyl-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 370 575

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 400 576

2′-Fluoro-4′-methyl-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 370 577

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (2-hydroxy-1-methyl-ethyl)- amide 386 578

2′-Fluoro-4′-methyl-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 384 579

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)- amide 396 580

2′-Fluoro-4′-methyl-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((R)-1-methyl-2- morpholin-4-yl-ethyl)- amide 481 581

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)- amide 386 582

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((R)-2- hydroxy-1-methyl-ethyl)- amide 400 583

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acidcyclopropylamide 368 584

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acidcyclopropylamide 382 585

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 400 586

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 400 587

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 414 588

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl biphenyl-3-carboxylicacid cyclopropylamide 382 589

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 464 590

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid ((R)-1-methyl-2- morpholin-4-yl-ethyl)- amide 469 591

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((R)-2-methoxy-1-methyl- ethyl)-amide 380 592

4′-Methyl-5-(5-methyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((R)-2- methoxy-1-methyl- ethyl)-amide 366 593

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((R)-2- methoxy-1-methyl- ethyl)-amide 394 594

5-(5-Methoxymethyl- tetrazol-1-yl)-4-methyl- biphenyl-3-carboxylic acid((R)-2-methoxy-1- methyl-ethyl)-amide 396 595

5-(5-Ethoxymethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylic acid((R)-2-methoxy-1- methyl-ethyl)-amide 410 596

4′-Methyl-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3- carboxylicacid ((R)-2- methoxy-1-methyl- ethyl)-amide 420 597

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((R)-2- methoxy-1-methyl- ethyl)-amide 408 598

5-(5-Isobutyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 442 599

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-hydroxymethyl-2-methyl- propyl)-amide 422 600

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acidcyclopropylamide 348 601

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1,1-dimethyl- ethyl)-amide 380 602

2′-Chloro-4′-fluoro-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3-carboxylic acid ((S)-2- methoxy-1-methyl- ethyl)-amide 458 603

2′-Chloro-4′-fluoro-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3-carboxylic acid (2- methoxy-1-methyl- ethyl)-amide 458 604

2′-Chloro-4′-fluoro-5-(5- trifluoromethyl-tetrazol- 1-yl)-biphenyl-3-carboxylic acid [(R)-2- (1,1-dioxo-1λ⁶- thiomorpholin-4-yl)-1-methyl-ethyl]-amide 561 605

5-(5-Ethyl-tetrazol-1-yl)- 2′,4′-difluoro-biphenyl-3- carboxylic acid((R)-1- methyl-2-morpholin-4-yl- ethyl)-amide 457 606

2′,4′-Difluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylic acidcyclopropylamide 356 607

5-(5-Cyclopropyl- tetrazol-1-yl)-2′,4′- difluoro-biphenyl-3- carboxylicacid cyclopropylamide 382 608

5-(5-Cyclopropyl- tetrazol-1-yl)-2′,4′- difluoro-biphenyl-3- carboxylicacid (2- methoxy-1-methyl- ethyl)-amide 414 609

5-(5-Ethyl-tetrazol-1-yl)- 2′,4′-difluoro-biphenyl-3- carboxylic acid((S)-2- hydroxy-1-methyl-ethyl)- amide 388 610

5-(5-Cyclopropyl- tetrazol-1-yl)-2′,4′- difluoro-biphenyl-3- carboxylicacid ((R)-1- methyl-2-morpholin-4-yl- ethyl)-amide 469 611

2′,4′-Difluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylic acid((R)-1-methyl-2- morpholin-4-yl-ethyl)- amide 443 612

5-(5-Cyclopropyl- tetrazol-1-yl)-2′,4′- difluoro-biphenyl-3- carboxylicacid ((S)-2- hydroxy-1-methyl-ethyl)- amide 400 613

2′,4′-Difluoro-5-(5- isopropyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((R)-1-methyl-2- morpholin-4-yl-ethyl)- amide 471 614

3-(5-Ethyl-tetrazol-1-yl)- N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 367 615

N-((S)-2-Hydroxy-1- methyl-ethyl)-3-(5- isopropyl-tetrazol-1-yl)-5-(5-methyl-pyridin-2- yl)-benzamide 381 616

5-(5-Ethyl-tetrazol-1-yl)- 2′,4′-difluoro-biphenyl-3- carboxylic acidcyclopropylamide 370 617

2′,4′-Difluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylic acid((S)-2-hydroxy-1- methyl-ethyl)-amide 374 618

2′,4′-Difluoro-5-(5- isopropyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid cyclopropylamide 384 619

3-(5-Ethyl-tetrazol-1-yl)- N-(2-methoxy-1-methyl- ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide 381 620

5-(5-Ethyl-tetrazol-l-yl)- 2′,4′-difluoro-biphenyl-3- carboxylic acid(2- methoxy-1-methyl- ethyl)-amide 402 621

2′,4′-Difluoro-5-(5- isopropyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-hydroxy-l- methyl-ethyl)-amide 402 622

3-(5-Isopropyl-tetrazol-1- yl)-N-(2-methoxy-1- methyl-ethyl)-5-(5-methyl-pyridin-2-yl)- benzamide 395 623

2′,4′-Dichloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid(2- methoxy-1-methyl- ethyl)-amide 434 624

2′,4′-Dichloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid(2- hydroxy-1-methyl-ethyl)- amide 420 625

2′,4′-Dichloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((S)-2- hydroxy-1-methyl-ethyl)- amide 420 626

2′,4′-Dichloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((R)-1- methyl-2-morpholin-4-yl- ethyl)-amide 489 627

2′,4′-Dichloro-5-(5-ethyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid(1- pyrazin-2-yl-ethyl)-amide 484 628

2′,4′-Difluoro-5-(5- isopropyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 416 629

2′,4′-Difluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylic acid(2-methoxy-1- methyl-ethyl)-amide 388 630

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1- methyl-ethyl)-amide 120.0-121.0° C. 631

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-l- methyl-ethyl)-amide 412 632

2′-Fluoro-5-(5-isopropyl tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 446 633

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid ((R)-2-methoxy-1- methyl-ethyl)-amide 412 634

5-(5-Ethyl-tetrazol-l-yl)- 2′-fluoro-4′-methyl- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 384 635

5-(5-Ethyl-tetrazol-1-yl)- 2′-fluoro-4′-methyl- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 398 636

5-(5-Ethyl-tetrazol-1-yl)- 2′-fluoro-4′-methyl- biphenyl-3-carboxylicacid ((R)-2-methoxy-1- methyl-ethyl)-amide 398 637

5-(5-Ethyl-tetrazol-l -yl)- 4′-methyl-biphenyl-3- carboxylic acid [2-(1-acetyl-azetidin-3-yl)-1- methyl-ethyl]-amide 447 638

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-methyl-2-pyrazin-2-yl- ethyl)-amide 428 639

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-imidazol-1-yl-1-methyl- ethyl)-amide 416 640

5-(5-Ethyl-tetrazol-1-yt)- 4′-methyl-biphenyl-3- carboxylic acid (1-pyridazin-3-yl-ethyl)- amide 93.3- 96.6° C. 641

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(pyrazin- 2-ylmethyl)-amide 400 642

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[2-(3,5- dimethyl-pyrazol-1-yl)-1- methyl-ethyl]-amide 444 643

5-(5-Ethyl-tetrazol-l-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-methyl-2-pyrazol-1-yl- ethyl)-amide 416 644

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-2′-fluoro- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 418 645

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-2′-fluoro- biphenyl-3-carboxylicacid ((R)-2-methoxy-1- methyl-ethyl)-amide 418 646

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-2′-fluoro- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 404 647

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-2′-fluoro- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 404 648

4′-Chloro-5-(5-ethyl- tetrazol-1-yl)-2′-fluoro- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 452 649

4′-Chloro-2′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1- methyl-ethyl)-amide 432 650

4′-Chloro-2′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid ((R)-2-methoxy-1- methyl-ethyl)-amide 432 651

4′-Chloro-2′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (2-hydroxy-1- methyl-ethyl)-amide 418 652

4′-Chloro-2′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1- methyl-ethyl)-amide 418 653

4′-Chloro-2′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 466 654

4′-Chloro-2′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-methoxy-1- methyl-ethyl)-amide 404 655

4′-Chloro-2′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((R)-2-methoxy-1- methyl-ethyl)-amide 404 656

4′-Chloro-2′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 390 657

4′-Chloro-2′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 390 658

4′-Chloro-2′-fluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 438 659

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-ethyl)-amide 366 660

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]- amide 394 661

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(2-methyl-thiazol-4-yl)- ethyl]-amide 433 662

5-(5-Ethyl-tetrazol-1-yl)- 2′-fluoro-4′-methyl- biphenyl-3-carboxylicacid (2-hydroxy-1- methyl-ethyl)-amide 384 663

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid [2-(1-acetyl- azetidin-3-yl)-1-methyl- ethyl]-amide 481 664

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid {(R)-1-[bis-(2-hydroxy-ethyl)- carbamoyl]-ethyl}-amide 467 665

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((R)-1-methyl-2-pyrazin-2-yl- ethyl)-amide 428 666

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-2-methyl- propyl)-amide 380 667

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(1-cyano- cyclopropyl)-amide 373 668

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)- amide 366 669

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-ethyl)-amide 352 670

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-propyl)-amide 366 671

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid{1-[3-(2- chloro-phenyl)- [1,2,4]oxadiazol-5-yl]- ethyl}-amide 514 672

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(3-pyridin-4-yl- [1,2,4]oxadiazol-5-yl)- ethyl]-amide 481 673

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid {(R)-2-[bis-(2-hydroxy-ethyl)- amino]-1-methyl-ethyl}- amide 453 674

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[1-(3,5- dimethyl-1H-pyrazol-4- yl)-ethyl]-amide 430 675

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid((1S,2S)- 2-hydroxy-cyclopentyl)- amide 392 676

5-(5-Ethyl-tetrazol-l-yl)- 4′-methyl-biphenyl-3- carboxylic acid((1R,2S)- 2-hydroxy-cyclopentyl)- amide 392 677

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acidpyridazin-4-ylamide 386 678

5-(5-Ethyl-tetrazol-1-yl)- 2′-fluoro-4′-methyl- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 407 679

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid ((R)-2-hydroxy-1-methoxymethyl-ethyl)- amide 114.3- 115.0° C. 680

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((R)-2-hydroxy-1- methoxymethyl-ethyl)- amide 396 681

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((R)-2- hydroxy-1- methoxymethyl-ethyl)- amide 410 682

5-(5-Ethyl-tetrazol-1-yl)- 4-methyl-biphenyl-3- carboxylic acid (5-hydroxy-1,5-dimethyl- hexyl)-amide 436 683

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (5-hydroxy-1,5-dimethyl- hexyl)-amide 450 684

Methanesulfonic acid (R)-2-{[5-(5-ethyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carbonyl]- amino}-propyl ester 685

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (2,3-dihydroxy-propyl)-amide 382 686

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(pyrazin- 2-ylmethyl)-amide 414 687

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(2-methyl-2H-pyrazol-3-yl)- ethyl]-amide 172.8- 174.2° C. 688

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 96.9- 99.3° C. 689

2′,4′-Difluoro-5-(5- methyl-tetrazol-1-yl)- biphenyl-3-carboxylic acid(1-pyrazin-2-yl- ethyl)-amide 422 690

5-(5-Cyclopropyl- tetrazol-1-yl)-2′,4′- difluoro-biphenyl-3- carboxylicacid (1- pyrazin-2-yl-ethyl)-amide 448 691

2′,4′-Difluoro-5-(5- isopropyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 450 692

5-(5-Ethyl-tetrazol-1-yl)- 2′,4′-difluoro-biphenyl-3- carboxylic acid(1- pyrazin-2-yl-ethyl)-amide 436 693

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(thiazol- 5-ylmethyl)-amide 76.0- 79.0° C. 694

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-methyl-1H-imidazol-2- ylmethyl)-amide 205.0- 207.0° C. 695

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(6-chloro-pyrimidin-4-yl)- ethyl]-amide 75.0- 78.5° C. 696

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((S)-1-pyrazin-2-yl-ethyl)-amide 113.8- 117.7° C. 697

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(4-ethyl-4H-[1,2,4]triazol-3- yl)-ethyl]-amide 417 698

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[1-(1,3,5- trimethyl-1H-pyrazol-4- yl)-ethyl]-amide 430 699

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[1-(1,5- dimethyl-1H-pyrazol-4- yl)-ethyl]-amide 416 700

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid[1-(1,3- dimethyl-1H-pyrazol-4- yl)-ethyl]-amide 416 701

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid{1-[3-(2- methoxy-ethyl)- [1,2,4]oxadiazol-5-yl]- ethyl}-amide 448 702

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(3-pyridin-3-yl- [1,2,4]oxadiazol-5-yl)- ethyl]-amide 483 703

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid [1-(1H-tetrazol-5-yl)-ethyl]- amide 390 704

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-phenyl-cyclopropyl)- amide 424 705

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid {(R)-2-[(2-hydroxy-ethyl)- methyl-amino]-1-methyl- ethyl}-amide 439 706

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acidtert- butylamide 378 707

4′-Methyl-5-tetrazol-1-yl- biphenyl-3-carboxylic acid[(R)-2-(3-chloro-2- fluoro-propylamino)-1- methyl-ethyl]-amide 447 708

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(R)-2-(3- chloro-2-fluoro- propylamino)-1-methyl- ethyl]-amide 473 709

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid [(R)-2-(3-chloro-2- fluoro-propylamino)-1- methyl-ethyl]-amide 493710

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid ((R)-2-methoxy-1- methyl-ethyl)-amide 428 711

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1- methyl-ethyl)-amide 414 712

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1- methyl-ethyl)-amide 414 713

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 462 714

5-(5-Isopropyl-tetrazol-1- yl)-4-methyl-biphenyl-3- carboxylic acidcyclopropylamide 396 715

2′-Chloro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 462 716

2′-Fluoro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 446 717

2′-Fluoro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 398 718

4′-Chloro-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl-ethyl)-amide 448 719

4′-Chloro-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((S)-2- hydroxy-1-methyl-ethyl)- amide 720

4′-Methyl-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 75.3- 81.0° C. 721

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((R)-1- pyrazin-2-yl-ethyl)-amide 83.0- 86.9° C. 722

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((S)-1- pyrazin-2-yl-ethyl)-amide 95.5- 99.0° C. 723

2′-Chloro-5-(5-ethyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid (5-methyl-pyrazin-2- ylmethyl)-amide 448 724

2′-Chloro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (5-methyl-pyrazin-2- ylmethyl)-amide 462 725

2′-Fluoro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (5-methyl-pyrazin-2- ylmethyl)-amide 446 736

4′-Chloro-5-(5-propyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 448 727

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1H-pyrazol-3-ylmethyl)- amide 190.1- 191.3° C. 728

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 152.0- 154.5° C. 729

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 71.0-76.0° C. 730

2'-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 85.0-90.0° C. 731

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 448 732

4′-Chloro-2′-fluoro-5-(5- isopropyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2- ylmethyl)-amide 80.1-86.0° C. 733

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(1-cyano- cyclopropyl)-amide 85.0- 89.6° C. 734

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(pyridin- 2-ylmethyl)-amide 399 735

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(pyridin- 3-ylmethyl)-amide 399 736

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(pyridin- 4-ylmethyl)-amide 399 737

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4-methyl- biphenyl-3-carboxylicacid (pyridin-2- ylmethyl)-amide 431 738

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (pyridin-3- ylmethyl)-amide 431 739

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (pyridin-4- ylraethyl)-amide 431 740

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid{1-[4-(2- methoxy-ethyl)-4H- [1,2,4]triazol-3-yl]- ethyl}-amide 88.0-94.0° C. 741

4′-Chloro-2′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (5-methyl-pyrazin-2- ylmethyl)-amide 52.0- 55.0° C. 742

4′-Chloro-2′-fluoro-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 58.0- 60.3° C. 743

3-(6-Chloro-pyridazin- yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 450 744

3-(6-Chloro-pyridazin-3- yl)-N-((S)-2-hydroxy-1- methyl-ethyl)-5-(5-isopropyl-tetrazol-1-yl)- benzamide 402 745

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)-amide 77.0- 83.0° C. 746

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-pyridin-2-yl-ethyl)-amide 413 747

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-pyridin-3-yl-ethyl)-amide 413 748

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (1-pyridm-4-yl-ethyl)-amide 413 749

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyridin-2-yl- ethyl)-amide 461 750

2′-Chloro-5-(5-isopropyl tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid (1-pyridin-3-yl- ethyl)-amide 461 751

2′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyridin-4-yl- ethyl)-amide 461 752

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyridin-2-yl- ethyl)-amide 445 753

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyridin-3-yl- ethyl)-amide 445 754

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyridin-4-yl- ethyl)-amide 445 755

2′-Fluoro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyridin-2-yl- ethyl)-amide 445 756

2′-Fluoro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyridin-3-yl- ethyl)-amide 445 757

2′-Fluoro-4′-methyl-5-(5- propyl-tetrazol-1-yl)- biphenyl-3-carboxylicacid (1-pyridin-4-yl- ethyl)-amide 445 758

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(4-amino- 2-methyl-pyrimidin-5- ylmethyl)-amide 443 759

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(2-amino- pyridin-4-ylmethyl)- amide 428 760

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid(6-amino- pyridin-3-ylmethyl)- amide 428 761

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(R)-2-(3- hydroxy-azetidin-1-yl)-1- methyl-ethyl]-amide 435 762

2′-Fluoro-5-(5-isopropyl tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid [(R)-2-(3-hydroxy- azetidin-1-yl)-1-methyl- ethyl]-amide 453 763

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(R)-2-(3- fluoro-azetidin-1-yl)-1- methyl-ethyl]-amide 437 764

2′-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid [(R)-2-(3-fluoro- azetidin-1-yl)-1-methyl-ethyl]-amide 455 765

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(S)-1-(6- methoxy-pyridazin-3-yl)- ethyl]-amide 104.9- 109.0° C. 766

5-(5-Ethyl-tetrazol-1-yl)- 4-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1-pyridin-3-yl- ethyl)-amide 429 767

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(3-oxo- 2,3-dihydro-isoxazol-5- ylmethyl)-amide 419 768

5-(5-Isopropyl-tetrazol-1- yl)-4'-methyl-biphenyl-3- carboxylic acid (3-methyl-thiophen-2- ylmethyl)-amide 432 769

5-(5-Isopropyl-tetrazol-1- yl)-4-methyl-biphenyl-3- carboxylic acid[1-(3- fluoro-phenyl)- cyclopropyl]-amide 456 770

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (5-methyl-[1,3,4]oxadiazol- 2-ylmethyl)-amide 418 771

5-(5-Isopropyl-tetrazol-l- yl)-4′-methyl-biphenyl-3- carboxylic acid (4-methyl-isoxazol-3- ylmethyl)-amide 417 772

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(oxazol- 2-ylmethyl)-amide 403 773

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid [1-methyl-2-(3- trifluoromethyl-pyrazol- 1-yl)-ethyl]-amide 498 774

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(1- methyl-1H-pyrazol-3-yl)- ethyl]-amide 444 775

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid [1-methyl-2-(3-methyl- pyrazol-1-yl)-ethyl]- amide 444 776

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid [1-methyl-2-(5-methyl-3- trifluoromethyl-pyrazol- 1-yl)-ethyl]-amide 512777

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[2-(5- cyclopropyl-3- trifluoromethyl-pyrazol- 1-yl)-1-methyl-ethyl]-amide 538 778

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(4- fluoro-phenyl)- cyclopropyl] -amide 456 779

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-cyclopropyl-ethyl)-amide 390 780

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(imidazo[2,1-b]thiazol-6- ylmethyl)-amide 458 781

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[1-(2- methyl-thiazol-4-yl)- ethyl]-amide 433 782

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-thiazol-4-yl-ethyl)-amide 419 783

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-propyl-2H-pyrazol-3- ylmethyl)-amide 444 784

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[2-(1,3- dimethyl-1H-pyrazol-4- yl)-1-methyl-ethyl]- amide 458 785

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-methyl-2H-pyrazol-3- ylmethyl)-amide 444 786

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid(2-ethyl- 2H-pyrazol-3-ylmethyl)- amide 458 787

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(R)-2-(3- methoxy-azetidin-1-yl)- 1-methyl-ethyl]-amide 449 788

2-Fluoro-5-(5-isopropyl- tetrazol-1-yl)-4′-methyl- biphenyl-3-carboxylicacid [(R)-2-(3-methoxy- azetidin-1-yl)-1-methyl- ethyl]-amide 467 789

5-[5-(1-Hydroxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 382 790

5-[5-(1-Hydroxy-ethyl)- tetrazol-1-yl]-4-methyl- biphenyl-3-carboxylicacid ((R)-2-methoxy-1- methyl-ethyl)-amide 396 791

5-[5-(1-Hydroxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 430 792

5-(5-Ethyl-tetrazol-1-yl)- 4′-methyl-biphenyl-3- carboxylic acid (6-methyl-pyridin-3- ylmethyl)-amide 427 793

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid (6-methyl-pyridin-3- ylmethyl)-amide 441 794

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid[(R)-1-(6- methoxy-pyridazin-3-yl)- ethyl]-amide 458 795

5-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid ((R)-2-methoxy-1- methyl-ethyl)-amide 410 796

5-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid ((S)-2-hydroxy-1- methyl-ethyl)-amide 396 797

5-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (1-pyrazin-2-yl- ethyl)-amide 444 798

5-[5-(1-Methoxy-ethyl)- tetrazol-1-yl]-4′-methyl- biphenyl-3-carboxylicacid (5-methyl-pyrazin-2- ylmethyl)-amide 444 799

5-(5-Isopropyl-tetrazol-1- yl)-4′-methyl-biphenyl-3- carboxylic acid((S)-2- hydroxy-1,2-dimethyl- propyl)-amide 86.0- 89.0° C. 800

4′-Chloro-5-(5-isopropyl- tetrazol-1-yl)-biphenyl-3- carboxylic acid((S)-1- pyrazin-2-yl-ethyl)-amide 448 801

3-(5-Isopropyl-tetrazo-1- yl)-N-(8-methyl- imidazo[1,2-a]pyridin-2-ylmethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 467 802

N-(1H-Imidazo[4,5- b]pyridin-2-ylmethyl)-3- (5-isopropyl-tetrazol-l-yl)-5-(5-methyl-pyridin- 2-yl)-benzamide 454 803

3-(5-Bromo-pyridin-2 yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 494 804

3-(5-Bromo-pyridin-2- yl)-5-(5-isopropyl- tetrazol-1-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 494

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula (I), wherein R⁶, R¹¹, R¹² and R¹³ are asdefined herein.

In step 1 of Scheme A, nitrobenzoic acid a is subject to iodinationunder sulfuric acid conditions to afford iodo-nitrobenzoic acid b.Benzoic acid compound b is reacted with arylboronic acid compound c inthe presence of tetrakis-(triphenylphosphine)palladium catalyst toafford biphenyl acid compound d. The acid group of biphenyl acid d isprotected by esterification in step 3 to form biphenyl acid methyl estere. Biphenyl ester e is then subject to reduction to form biphenylaminefin step 4. A cyclization reaction is carried out in step 5 by treatingbiphenylamine f with sodium azide and acetal compound g to providebiphenyl tetrazole compound h. In step 6 the ester group of compound his hydrolyzed to give acid compound i. In step 7 an amide formation isachieved by reaction of biphenyl tetrazole compound i with amine j inthe presence of carbodiimide, to afford compound k, which is a compoundof formula I in accordance with the invention.

Many variations of Scheme A are possible and will suggest themselves tothose skilled in the art. The aryl boronic acid is shown in step 2 asbeing a phenyl boronic acid, but may be replaced by pyridinyl boronicacids in other embodiments of the invention. In many embodiments aminecompound h is a secondary amine with specific stereochemistry. Incertain embodiments the amide formation of step 7 may be carried outprior to tetrazole formation in step 5. Methanol in step 3 may bereplaced with other lower alcohols.

Scheme B below illustrates another synthetic procedure usable to preparespecific compounds of formula (I), wherein R⁶, R¹¹, R¹² and R¹³ are asdefined herein.

In step 1 of Scheme B, biphenyl amine compound f undergoes anN-acylation by reaction with anhydride m to provide amide compound n.Anhydride m may be replaced with the corresponding acid chloride in manyembodiments. Amide n undergoes cyclization in step 2 by reaction withsodium azide to yield biphenyl tetrazole compound h. Following theprocedure of Scheme A above, compound h may then be hydrolyzed in step 3to form acid compound i, which is reacted amine j to afford compound k,which is a compound of formula I as noted above.

As in Scheme A, many variations of Scheme B are possible and willsuggest themselves to those skilled in the art.

Specific details for producing compounds of the invention are describedin the Examples section below.

Utility

The compounds of the invention are usable for the treatment of a widerange of genitorurinary diseases, conditions and disorders, includingurinary tract disease states associated with bladder outlet obstructionand urinary incontinence conditions such as reduced bladder capacity,frequency of micturition, urge incontinence, stress incontinence,bladder hyperreactivity, benign prostatic hypertrophy (BPH),prostatitis, detrusor hyperreflexia, urinary frequency, nocturia,urinary urgency, overactive bladder, pelvic hypersensitivity,urethritis, prostatitis, pelvic pain syndrome, prostatodynia, cystitis,and idiophatic bladder hypersensitivity, and other symptoms related tooveractive bladder.

The compounds of the invention are expected to find utility asanalgesics in the treatment of diseases and conditions associated withpain from a wide variety of causes, including, but not limited to,inflammatory pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injuries (including fractures andsports injuries), and pain associated with functional bowel disorderssuch as irritable bowel syndrome.

Further, compounds of the invention are useful for treating respiratorydisorders, including chronic obstructive pulmonary disorder (COPD),asthma, bronchospasm, and the like.

Additionally, compounds of the invention are useful for treatinggastrointestinal disorders, including Irritable Bowel Syndrome (IBS),Inflammatory Bowel Disease (IBD), biliary colic and other biliarydisorders, renal colic, diarrhea-dominant IBS, pain associated with GIdistension, and the like.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. The preferred manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules.

A solid carrier may be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

ABBREVIATIONS

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane/methylene chloride

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

EDCI 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide

EtOAc ethyl acetate

EtOH ethanol

gc gas chromatography

HMPA hexamethylphosphoramide

HOBt N-Hydroxybenzotriazole

hplc high performance liquid chromatography

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

NMM N-methyl-morpholine

NMP N-methyl pyrrolidinone

TEA triethylamine

THF tetrahydrofuran

LDA lithium diisopropylamine

TLC thin layer chromatography

Preparation 1 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid

The synthetic procedure used in this preparation is outlined below inScheme C.

Step 1 3-Iodo-5-nitro-benzoic acid

To a stirred solution of iodine (137.95 g, 0.5436 mmol) in fumingsulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g, 0.3866mmol) at room temperature. The reaction mixture was slowly heated to 85°C. overs 2 hours and stirred at the same temperature for another 12hours. The reaction mixture was cooled to room temperature and pouredinto ice, and the aqueous solution was extracted with dichloromethane.The organic phase was separated and washed with water, 2.0 M solution ofNa₂S₂O₃ and brine, and then dried over Na₂SO₄. Solvent was removed underreduced pressure to yield 3-iodo-5-nitrobenzoic acid as slight yellowsolid 111 g, yield 98%. MS (M+H)=294.

Step 2 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid

To a stirred solution of 3-iodo-5-nitrobenzoic acid (15.48 g, 52.83mmol) and Pd(Ph₃P)₄ (1.84 g, 1.69 mmol) in 300 ml of toluene and 50 mlof ethanol was added p-tolylboronic acid (7.87 g, 58.11 mmol) and asolution of Cs₂CO₃ (18.89 g, 58.11 mmol) in 20 ml water at roomtemperature. The reaction was brought to reflux for 18 hours and thencooled to room temperature.

To the solution was added 2N NaOH, and the reaction mixture was stirredfor 30 minutes. The organic phase was separated, and the aqueous phasewas adjusted to PH <4 using 12N HCl. The resulting solid precipitate wasfiltered and washed with toluene to afford 13.2 g of4′-Methyl-5-nitro-biphenyl-3-carboxylic acid as light yellow solid(97.2%). MS (M+H)=258.

Step 3 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester

To a solution of 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid (10.00 g,0.039 mol) in methanol was added SOCl₂ (5.09 g, 0.043 mol) at 0° C. Thereaction mixture was allowed to warm to room temperature and was thenheated to reflux for 2 hours. The solvent was removed in vacuo to afford4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (9.72 g, 92%)as light yellow solid. MS (M+H)=273.

Step 4 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester

To a solution of 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methylester (10.00 g, 36.9 mmol) in methanol was added SnCl₂ (27.98 g, 147.6mmol) at room temperature. The reaction mixture was refluxed for 3hours, then cooled. Solvent was removed in vacuo and the residue wasdissolved in H₂O, then basified by addition of Na₂CO₃ to pH=9. Themixture was extracted by CH₂Cl₂, and the organic phase was washed withwater followed by brine, and dried over Na₂SO₄. The solvent was removedunder vacuum to give 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methylester (8.48 g, 95%) as yellow oil. MS (M+H)=242.

Step 5 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester

To a solution of 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methylester (10 g, 41.5 mmol) and NaN₃ (4.99 g, 76.76 mmol) in AcOH (80 mL)was added HC(OEt)₃ (29.5 g, 199.2 mmol) at room temperature, then heatedto reflux for 4 h. The solvent was removed in vacuo and the residue waspurified by silica-gel chromatography to give4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester aslight yellow solid (11.22 g, 92%). MS (M+H)=295.

Step 6 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid

A solution of LiOH H₂O (1.86 g, 44.2 mmol) in H₂O (40 mL) was addeddropwise to a suspension of4′Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester (10 g,34 mmol) in THF (25 mL) at 0° C. The reaction mixture was allowed towarm to room temperature and was stirred until the reaction solutionturned clear. Solvent was removed under vacuum and the aqueous solutionwas acidified by addition of 10% HCl to pH=3. The resulting precipitatewas collected and dried to afford4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid as white solid(8.85 g, 93%). MS (M+H)=281.

Similarly prepared, using the appropriately substituted phenyl boronicacids in step 2, were:

2′-Fluoro-4′-methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MS(M+H)=299;

2′-Chloro-4′-methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MS(M+H)=315;

2′,4′-Difluoro-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MS (M+H)=303;

2′-Chloro-4′-fluoro-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MS(M+H)=319;

2′,4′-Dichloro-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MS (M+H)=335;and

4′-Chloro-2′-fluoro-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MS(M+H)=319.

Preparation 2 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid

The synthetic procedure used in this preparation is outlined below inScheme D.

Step 1 3-Iodo-5-nitro-benzoic acid methyl ester

To a solution of 3-iodo-5-nitrobenzoic acid (20.00 g, 0.068 mol) inmethanol (50 mL) was added SOCl₂ (5.45 mL, 0.075 mol) at 0° C. Thereaction mixture was allowed to warm to room temperature and was thenheated to reflux for 2 hours. The reaction was cooled and solvent wasremoved in vacuo to afford 3-Iodo-5-nitro-benzoic acid methyl ester aslight yellow solid (20.67 g, 99%). MS (M+H)=309.

Step 2 3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacid methyl ester

To a stirred solution of 3-Iodo-5-nitro-benzoic acid methyl ester (5.0g, 0.016 mol), bis(pinacolato)diborane (4.55 g, 0.018 mol) and KOAc(4.80 g, 0.049 mol) in DMSO (50 mL) was added PdCl₂(dpf)₂ (0.40 g, 0.50mmol). The mixture was flushed with N₂ and heated to 80 C for 2 h. Afterthe reaction mixture was cooled down to room temperature, H₂O (20 mL)was added and the mixture was extracted with Et₂O (3×30 mL). The organiclayer was separated and washed with H₂O, brine and dried over Na₂SO₄.Solvent was removed and the residue was purified by columnchromatography (EtOAc/hexane=1:3) to afford3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester as a white solid (3.30 g, 67%) MS (M+H)=308.

Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester

To a solution of3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester (100 mg, 0.326 mmol), 2-bromo-5 methyl-pyridine (56 mg,0.326 mmol), K₃PO₄ (138 mg, 0.652 mmol) in dimethoxy ethylene (3 mL) andwater (1 mL) was added Pd(Pph₃)₄ (11.3 mg, 0.001 mmol). The mixture wasflushed with N₂ and heated under microwave at 130° C. for 30 minutes.The reaction mixture was cooled, solvent was removed under reducedpressure, and the residue was purified by column chromatography(EtOAc/hexane=1:3) to afford 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoicacid methyl ester as a white solid (50 mg, 56%). MS (M+H)=273.

Step 4 3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester

To a solution of 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methylester (410 mg, 36.9 mmol) in methanol was added SnCl₂ (1.36 g, 6.03mmol) at room temperature. The reaction mixture was refluxed for 3 hoursand then cooled. Solvent was removed in vacuo and the residue wasdissolved in H₂O and basified by Na₂CO₃ to pH=9. The mixture wasextracted with CH₂Cl₂, and the organic phase was washed with water,brine, and dried over Na₂SO₄. The solvent was removed under vacuum togive 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (362 mg, 100%) as yellow oil. MS (M+H)=244.

Step 5 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methylester

To a solution of 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methylester (362 mg, 1.51 mmol) and NaN₃ (182 g, 2.8 mmol) in AcOH was addedHC(OEt)₃ (1074 mg, 7.25 mmol) at room temperature. The reaction mixturewas heated to reflux for 4 hours and then cooled to room temperature.The solvent was removed in vacuo and the residue was purified bysilica-gel chromatography to give3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester as alight yellow solid (440 mg, 100%). MS (M+H)=296.

Step 6 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid

A solution of LiOH hydrate (82 mg, 1.94 mmol) in H₂O (7 mL) was addeddropwise to a suspension of3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (440mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowedto warm to room temperature and was stirred until the reaction solutionturned into clear. Solvent was removed under vacuum and the resultingaqueous solution was acidified by 10% HCl to pH=6-7. The resultingprecipitate was collected and dried to afford3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid as a yellow solid(390 mg, 93%). MS (M+H)=282.

Similarly prepared was3-(5-Fluoro-pyridin-2-yl)-N-(1-methyl-2-morpholin-4-yl-ethyl)-5-tetrazol-1-yl-benzamide,MS (M+H)=412.

Similarly prepared, but omitting step 6, was3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid, MS (M+H)=229.

Similarly prepared, but replacing 2-bromo-5-methyl-pyridine with2,5-dichloro-pyridine in step 3 and omitting step 6, was3-amino-5-(chloro-pyridin-2-yl)-benzoic acid, MS (M+H)=249.

Preparation 3 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-A-benzoicacid

The synthetic procedure used in this preparation is outlined below inScheme E.

Step 1 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-nitro-benzoic acid methylester

To a 25 ml round-bottomed flask was added 2-Hydroxy-4-methylpyridine(17.9 mg, 0.164 mmol), 3-Iodo-5-nitro-benzoic acid methyl ester (40 mg,0.137 mmol), CuI (5.2 mg, 0.027 mmol) and 1,4-dioxane (10 ml). Thereaction mixture was stirred for 5 minutes to the dissolve2-Hydroxy-4-methylpyridine and 3-iodo-5-nitro-benzoic acid methyl ester,after which 1,10-phenanthroline (9.84 mg, 0.055 mmol) was added,followed by K₃PO₄ (174 mg, 0.082 mmol). The reaction mixture was flushedwith N₂, and heated to 110° C. for 24 hours. After cooling to roomtemperature, the mixture was diluted with H₂O, and extracted with ethylacetate. The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash chromatography to give3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-nitro-benzoic acid methyl ester(39.45 mg, 61%) as light yellow solid. MS (M+H)=289.

Step 2 3-Amino-5-(4-Methyl-2-oxo-2H-pyridin-1-yl)benzoic acid methylester

To a solution of 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-nitro-benzoic acidmethyl ester (1000 mg, 3.47 mmol) in methanol was added SnCl₂ (2.63 g,13.9 mmol) at room temperature. The reaction mixture was refluxed for 3hours, then cooled to room temperature. Solvent was removed in vacuo,and the residue was dissolved in H₂O and basified by addition of Na₂CO₃to pH=9. The mixture was extracted with CH₂Cl₂, and the combined organicphase was washed with water, brine, and dried over Na₂SO₄. Solvent wasremoved under vacuum to give3-Amino-5-(4-Methyl-2-oxo-2H-pyridin-1-yl)benzoic acid methyl ester (895mg, 100%) as yellow solid. MS (M+H)=260.

Step 3 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)5-tetrazol-1-yl-benzoic acidmethyl ester

To a solution of 3-Amino-5-(4-Methyl-2-oxo-2H-pyridin-1-yl)benzoic acidmethyl ester (500 mg, 1.93 mmol) and NaN₃ (233 g, 3.58 mmol) in AcOH wasadded HC(OEt)₃ (1378.6 mg, 9.3 mmol) at room temperature. The reactionmixture was heated to reflux for 4 hours and then cooled to roomtemperature. The solvent was removed in vacuo and the residue waspurified by silica-gel chromatography to give3-(4-Methyl-2-oxo-2H-pyridin-1-yl)5-tetrazol-1-yl-benzoic acid methylester as a light yellow solid (602 mg, 100%). MS (M+H)=312.

Step 4 3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid

A solution of LiOH H₂O (95 mg, 2.25 mmol) in H₂O (7 mL) was addeddropwise to a suspension of3-(4-methyl-2-oxo-2H-pyridin-1-yl)5-tetrazol-1-yl-benzoic acid methylester (500 mg, 1.61 mmol) in THF (4 mL) at 0° C. The reaction mixturewas allowed to warm to room temperature and was stirred until thereaction solution turned into clear. Solvent was removed under vacuumand the aqueous solution was acidified by addition of 10% HCl to pH=2.The resulting precipitate was collected and dried to afford3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid asyellow solid (453 mg, 95%). MS (M+H)=298.

Preparation 43-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide

The synthetic procedure used in this preparation is outlined below inScheme F.

Step 1 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide

EDCI (7.07 g, 36.9 mmol) was added in one portion to a stirred solutionof 3-Iodo-5-nitro-benzoic acid (2.31 g, 24.6 mmol), HOBt (4.985 g, 36.9mmol), 2-Amino-1-methoxypropane (2.73 ml, 24.6 mmol) and NMP (4.06 ml36.9 mmol) in CH₂Cl₂ (120 ml) and DMF (10 ml) at 0° C. The reaction wasallowed to warm to room temperature and was stirred over night. Thereaction mixture was then washed with 2N NaOH, water, brine, and driedover Na₂SO₄. Solvent was removed in vacuo to give 2.50 g of3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide as a yellow solid,MS (M+H)=365. This material was used without further purification.

Step 2 3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium

To a solution of 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide(8.05 g, 20.5 mmol) in methanol was added SnCl₂ (17.34 g, 76.87 mmol) atroom temperature. The reaction mixture was refluxed for 3 hours. Solventwas removed in vacuo and the residue was dissolved in H₂O, then basifiedby addition of Na₂CO₃ to pH=9. The mixture was extracted with CH₂Cl₂,and the organic phase was washed with water, brine, and dried overNa₂SO₄. The solvent was removed under vacuum to give3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium (7.40 g,92.5%) as yellow oil. MS (M+H)=336.

Step 3 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide

To a solution of3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium (7.47 g,22.4 mmol) and NaN₃ (2.68 g, 41.2 mmol) in AcOH (100 mL) was addedHC(OEt)₃ (18.3 mL, 110 mmol) at room temperature. The reaction mixturewas brought to reflux for 4 hours, then cooled to room temperature. Thesolvent was removed in vacuo and the residue was purified by silica-gelchromatography to give3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide as a whitesolid (6.30 g, 72%). MS (M+H)=388.

Similarly prepared using the appropriate amines in step 1 were:

N-(1-Furan-2-yl-ethyl)-3-iodo-5-tetrazol-1-yl-benzamide, MS (M+H)=410;and

3-Iodo-N-(1-methyl-2-morpholin-4-yl-ethyl)-5-tetrazol-1-yl-benzamide, MS(M+H)=443.

Preparation 5 (S)-2-Methoxy-1-methyl-ethylamine

The synthetic procedure used in this preparation is outlined below inScheme G.

Step 1 (S)-Boc-2-amino-propanol

D-Alanine (3.5 g, 39.3 mmol) was added in small portions to a suspensionof LiAlH₄ (2.89 g, 76.26 mmol) in refluxing THF. Refluxing continued for12 hours, then the reaction mixture was cooled to 0° C., and excessreagent was quenched by careful addition of an aqueous 15% NaOH solution(3 ml) and water (9 ml). After stirring at room temperature for 10minutes, a solution of (Boc)₂O (8.31 g, 38.13 mmol) in CH₂Cl₂ (40 ml)was added. The reaction mixture was stirred at 60° C. for 6 hours,cooled to room temperature, filtered through a pad of anhydrous Na₂SO₄,and the filtrate concentrated under vacuum. Purification of the residueby silica-gel column chromatography afforded (S)-Boc-2-amino-propanol asa white solid, yield: 63%. MS (M+H)=176.

Step 2 (S)-Boc-2-methoxy-1-methyl-ethylamine

To a solution of (S)-Boc-2-amino-propanol (2.00 g, 11.4 mmol) wassuccessively added Ag₂O (5.89 g, 25.4 mmol) and Methyl iodide (16.00 g,112.7 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 2 days. Solid was filtered off and the filtrate wasconcentrated under vacuum to afford(S)-Boc-2-methoxy-1-methyl-ethylamine as a colorless oil that was usedwithout further purification.

Step 3 (S)-2-methoxy-1-methyl-ethylamine

(S)-Boc-2-methoxy-1-methyl-ethylamine was dissolved in MeOH (40 mL) and3 M HCl (10 mL) was added. The reaction mixture was stirred overnight atroom temperature, then solvent was removed under reduced pressure andthe residue was co-evaporated with additional EtOH (20 mL) to afford(S)-2-methoxy-1-methyl-ethylamine as light-brown oil in hydrochlorideform (1.42 g, 100%). MS (M+H)=90.

Similarly prepared was (S)-2-ethoxy-1-methyl-ethylamine.

Similarly prepared from L-alanine were (R)-2-methoxy-1-methyl-ethylamineand (R)-2-ethoxy-1-methyl-ethylamine.

Preparation 6 (S)-1-Methyl-2-morpholin-4-yl-ethylamine

The synthetic procedure used in this preparation is outlined below inScheme H.

Step 1 Methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester

To a solution of (S)-Boc-2-amino-propanol (4.91 g, 0.028 mol), Et₃N (1.5equiv.) in CH₂Cl₂ at 0° C. was added methanesulfonyl chloride (1.1-1.2equiv). The reaction was stirred at 0° C. for 30 minutes. Water (5 ml)was added and the organic layer was separated, washed with saturatedaqueous NaHCO₃, brine, and dried with MgSO₄. Solvent was removed undervacuum to afford methanesulfonic acid 2-tert-butoxycarbonylamino-propylester as a white solid, yield: 98%. MS (M+H)=254.

Step 2 (1-Methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester

To a solution of methanesulfonic acid 2-tert-butoxycarbonylamino-propylester (23 mmol) in CH₃CN (20 mL) was added morpholine (28 mmol) andK₂CO₃ (23 mmol) at room temperature. The reaction mixture was brought to50° C. and kept at the same temperature overnight. The reaction mixturewas cooled and solvent was removed under reduced pressure, and theresidue was treated with CH₂Cl₂ (50 mL) and H₂O (50 mL). The organiclayer was separated and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic layer was dried over Na₂SO₄. Solvent was removed underreduced pressure and the residue was purified by column chromatography(ethyl acetate) to afford (1-methyl-2-morpholin-4-yl-ethyl)-carbamicacid tert-butyl ester as viscous liquid, yield: 62%. MS (M+H)=245.

Step 3 (S)-1-Methyl-2-morpholin-4-yl-ethylamine

To a solution of (1-methyl-2-morpholin-4-yl-ethyl)-carbamic acidtert-butyl ester (0.30 g, 1.22 mmol) in methanol (10 mL) was added 2NHCl (5 mL) at 0° C. The reaction mixture was allowed to warm to roomtemperature and was stirred overnight. The solvent was removed undervacuum to give (S)-1-Methyl-2-morpholin-4-yl-ethylamine as a lightyellow solid (250 mg, 96%). MS (M+H)=145.

Similarly prepared were (S)-1-Methyl-2-thiomorpholin-4-yl-ethylamine,(S)-1-[4-(2-Amino-propyl)-piperazin-1-yl]-ethanone,(S)-1-(2-Amino-propyl)-piperidin-4-ol,(S)-1-(2-Amino-propyl)-piperidin-3-ol,(S)-1-Methyl-2-(4-methyl-piperazin-1-yl)-ethylamine,(S)-1-Methyl-2-(4-methanesulfonyl-piperazin-1-yl)-ethylamine,(S)-4-(2-Amino-propyl)-piperazin-2-one,1-Methyl-2-piperidin-1-yl-ethylamine,1-(2-Amino-propyl)-pyrrolidin-3-ol,(S)-2-(4-Methoxy-piperidin-1-yl)-1-methyl-ethylamine,(S)-2-(3-Methoxy-piperidin-1-yl)-1-methyl-ethylamine,(S)-2-(4-Methanesulfonyl-piperidin-1-yl)-1-methyl-ethylamine, and other2-amino-1-heterocyclyl propanes.

Preparation 7(S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine

The synthetic procedure used in this preparation is outlined below inScheme I.

Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acidtert-butyl ester

To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH₂Cl₂was added thiomorpholine (2.29 g, 22.2 mmol) at 0° C. The reactionmixture was stirred at 0° C. overnight, then washed with 2% aqueousNaOH, water, brine, and dried over Na₂SO₄. The solvent was removed undervacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acidtert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.

Step 2[2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamicacid tert-butyl ester

To a solution of (1-methyl-2-oxo-2-thiomorphin-4-yl-ethyl)-carbamic acidter-butyl ester (5.0 g, 18.2 mmol) in CH₂Cl₂ was added m-CPBA (11.4 g,46.25 mmol) at 0° C. The reaction mixture was stirred at roomtemperature overnight. Solids were removed by filtration and thefiltrate was washed by Na₂S₂O₃ and dried over Na₂SO₄. Solvent wasremoved under vacuum to give[2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamicacid tert-butyl ester (5.6 g), yield 100%. MS (M+H)=307.

Step 3 2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one

To a solution of[2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamicacid tert-butyl ester (5.6 g, 18.2 mmol) in CH2Cl2 (70 mL) was addedtrifluoroacetic acid (5 mL) at 0° C. The reaction mixture was allowed towarm to room temperature and was stirred for 3 hours. After removal ofCH₂Cl₂ and excess trifluoroacetic acid under reduced pressure,2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g,yield 100%) was obtained as a white solid. MS (M+H)=207.

Step 4 (S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine

A mixture of2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g,18.2 mmol) and BH₃ (1 M in THF, 110 mL) was heated to reflux for 48 h,then cooled to room temperature and quenched by MeOH. The volatile wasremoved under vacuum. 2 N HCl (100 mL) was added to the residue andheated to reflux for 18 h. Solvent was removed under vacuum to give(S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine (4.5g) as white solid, yield 90%. MS (M+H)=193.

Preparation 8 1-Thiophen-3-yl-ethylamine

The synthetic procedure used in this preparation is outlined below inScheme J.

To a solution of 3-Acetylthiophene (2.0 g, 15.85 mmol) and ammoniumacetate (12.2 g, 158.5 mmol) in methanol (50 mL) was added sodiumcyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction mixturewas stirred overnight at room temperature. After removal of methanol,water (20 mL) was added to the residue and the resulting solution wasbasified by addition of sodium hydroxide to pH=13. The aqueous solutionwas extracted with dichloromethane and the combined organic phase wasdried over sodium sulfate. Removal of the solvent under reduced pressureafforded 1.5 g 1-thiophen-3-yl-ethylamine, yield: 75%. MS (M+H)=128.

Similarly prepared from the appropriate heteroaryl methyl ketones orphenyl methyl ketones were: 1-Pyridin-2-yl-ethylamine,1-Pyridin-3-yl-ethylamine, 1-Pyridin-4-yl-ethylamine,1-(2-Fluoro-phenyl)-ethylamine, 1-(3-Fluoro-phenyl)-ethylamine,1-(4-methanesulfonyl-phenyl)-ethylamine, 1-furan-2-yl-ethylamine,1-(5-methyl-furan)-2-yl-ethylamine, 1-thiazol-2-yl-ethylamine,1-thien-2-yl-ethylamine, 1-Pyrazin-2-yl-ethylamine,1-Pyrimidin-2-yl-ethylamine, 1-Pyridazin-4-yl-ethylamine, and other1-heteroaryl ethylamines and 1-aryl ethylamines.

Example 1 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid(1-methyl-2-morpholin-4-yl-ethyl)-amide

The synthetic procedure used in this example is outlined below in SchemeK.

EDCI (54.0 mg, 0.282 mmol) was added in one portion at 0° C. to asolution of 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (60.0mg, 0.214 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000mmol) in CH₂Cl₂ (3 mL). After the reaction stirred at 0° C. for 1 hour,(S)-1-Methyl-2-morpholin-4-yl-ethylamine (50.0 mg, 0.230 mmol) wasadded. The reaction mixture was allowed to warm to room temperature andwas stirred overnight. Solvent was removed under reduced pressure andthe residue was purified by column chromatography (EtOAc) to afford4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid(1-methyl-2-morpholin-4-yl-ethyl)-amide as a white solid (70 mg, 81%).MS (M+H)=407.

Additional compounds prepared by the procedure of Example 1, using theappropriate amine and tetrazole-biphenyl carboxylic acids are shown inTable 1.

Example 2 2′-Fluoro-4′-methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)-amide

The synthetic procedure used in this example is outlined below in SchemeL.

A mixture of N-(1-Furan-2-yl-ethyl)-3-iodo-5-tetrazol-1-yl-benzamide (60mg, 0.146 mmol), 2-fluoro-4-methyl-phenylboronic acid (27.1 mg, 0.176mmol), Cs₂CO₃ (0.35 mL, 0.5 N, 0.176 mmol) and Pd(Ph₃P)₄ (8.5 mg,0.00735 mmol) in toluene (1.5 mL) and THF (1.5 mL) was stirred undermicrowave heating for 30 minutes at 130° C. After reaction mixture wascooled down, the solvent was removed under vacuum and the residue waspurified by column chromatography (hexane/EtOAc=1:2) to afford2′-Fluoro-4′-methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid(1-furan-2-yl-ethyl)-amide as a white solid (57 mg, 98%). MS (M+H)=392.

Additional compounds prepared by the procedure of Example 2 are shown inTable 1.

Example 3 5-(1-Ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylicacid (2-methoxy-1-methyl-ethyl)-amide

The synthetic procedure used in this example is outlined below in SchemeM.

Step 1 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester

A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester(10.9 g, 45.2 mmol), iso-amyl nitrite (36.5 ml, 271.4 mmol) anddiiodomethane (23 ml, 271.4 mmol) was stirred at room temperature for 1hour. The mixture was then heated to 65° C. and kept at this temperaturefor 8 hours. The reaction mixture to room temperature and then added toa stirred solution of piperidine/CH₃CN (V:V=90 ml:90 ml). A vigorousexothermic reaction ensued. The excess volatile reagents were removed byrotary evaporation. The residue was diluted with ethyl acetate, washedwith 10% hydrochloric acid, water, brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography, eluting with n-hexane, followed by n-hexane/ethylacetate (20:1), giving 5-Iodo-4′-methyl-biphenyl-3-carboxylic acidmethyl ester as white yellow solid (10.5 g, 66%).

Step 2 5-Ethylcarbamoyl-4′-methyl-biphenyl-3-carboxylic acid methylester

A 20 mL of vial was charged with 5-iodo-4′-methyl-biphenyl-3-carboxylicacid methyl ester (500 mg, 1.42 mmol), Pd(OAc)₂ (9.6 mg, 0.043 mmol),Mo(CO)₆ (413.5 mg, 1.566 mmol), ethylamine (2.0 M in MeOH, 1.068 mL,2.136 mmol), DBU (426 uL, 2.848 mmol) and dry THF (10 mL). The vial wasimmediately capped with a Teflon septum under air and irradiated withmicrowaves to 100° C. for 15 minutes. After cooling, the reactionmixture was filtered through a short celite pad and the solvent, andexcess DBU was removed under reduced pressure. The residue was purifiedby preparative HPLC to afford 210 mg of5-ethylcarbamoyl-4′-methyl-biphenyl-3-carboxylic acid methyl ester(yield 50%). MS (M+H)=298.

Step 3 5-(1-Ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acidmethyl ester

Sodium azide (145.8 mg, 16.2 mmol) was added into a solution of5-ethylcarbamoyl-4′-methyl-biphenyl-3-carboxylic acid methyl ester (210mg, 0.7 mmol) and SiCl4 (0.62 mL, 5.4 mmol) in dry acetonitrile (14 mL).After the reaction was stirred at room temperature for 24 hours, thereaction mixture was poured into cold saturated aqueous Na₂CO₃ solution.This mixture was extracted with ethyl acetate and dried with anhydrousNa₂SO₄. Solvent was removed under reduced pressure to afford 200 mgs of5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid methylester (yield 89%). MS (M+H)=323.

Step 4 5-(1-Ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid

A solution of LiOH H₂O (39.1 mg, 0.931 mmol) in H₂O (8 mL) was addeddropwise to a suspension of5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid methylester (200 mg, 0.621 mmol) in THF (5 mL) at 0° C. The reaction mixturewas allowed to warm to room temperature and was stirred until themixture turned clear. THF was removed under vacuum and the aqueoussolution was acidified by 10% HCl to pH=3. The precipitate was collectedand dried to afford5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid aswhite solid (162 mg, 84%). MS (M+H)=309.

Step 5 5-(1-Ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide

EDCI (54.0 mg, 0.282 mmol) was added in one portion to a solution of5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid (70.0mg, 0.229 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000mmol) in CH₂Cl₂ (5 mL) at 0° C. After the reaction stirred at the sametemperature for 1 hour, 2-methoxy-1-methyl-ethylamine (64.3 mg, 0.72mmol) was added. The mixture was allowed to warm to room temperature andwas stirred overnight. Solvent was removed under reduced pressure andthe residue was purified by column chromatography to afford5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide as white solid (40 mg, 46%). MS(M+H)=380.

Additional compounds made by the above procedure are shown in Table 1.

Example 44′-Methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide

The synthetic procedure used in this example is outlined below in SchemeN.

Step 15-[1-Chloro-2,2,2-trifluoro-eth-(Z)-ylideneamino]-4′-methyl-biphenyl-3-carboxylicacid methyl ester

A mixture of CF₃COOH (5.19 mmol, 398 mL), PPh₃ (15.56 mmol, 4.08 g) andNEt₃ (6.22 mmol, 868 μL) in 10 mL of CCl₄ was stirred at 0° C. for 10minutes. 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.5g, 6.22 mmol) was then added to the reaction mixture and the mixture washeated to reflux for 2 hours. Solvent was removed under reduced pressureand the residue was purified by flash column chromatography, elutingwith n-hexane: ethyl acetate (10:1), giving the5-[1-chloro-2,2,2-trifluoro-eth-(Z)-ylideneamino]-4′-methyl-biphenyl-3-carboxylicacid methyl ester as light yellow oil (1.3 g, 60% yield).

Step 24′-Methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acidmethyl ester

A mixture of NaN₃ (481 mg, 7.4 mmol) and5-[1-chloro-2,2,2-trifluoro-eth-(Z)-ylideneamino]-4′-methyl-biphenyl-3-carboxylicacid methyl ester (1.3 g, 3.7 mmol) in 10 ml of dry ACN was stirred atroom temperature for 16 hours. The reaction mixture were poured intoice-cold aqueous Na₂CO₃ solution, extracted with ethyl acetate. Theorganic layer washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The resulting crude4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acidmethyl ester (1.34 g, 99% yield) was used directly in the next step.

Step 34′-Methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid

To a stirred solution of4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acidmethyl ester (3.7 mmol, 1.34 g) in 50 ml of THF was added a solution ofLiOH.H₂O (18.5 mmol, 776.3 mg) in 12 mL of water. The reaction mixturewas heated to reflux for 3.5 hours, then cooled to room temperature.Solvent was removed under reduced pressure, and the pH of the liquidresidue was adjusted to 2.0 by addition of 2N aqueous HCl solution. Themixture was extracted with ethyl acetate and the combined ethyl acetatelayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo togive 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylicacid as light yellow solid (1.25 g, 97% yield).

Step 44′-Methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide

4′-Methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide was reacted with2-methoxy-1-methyl-ethylamine using the procedure of step 4 of Example 3to give4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylicacid. MS (M+H)=420.

Similarly prepared, but replacing5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester with3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester in step 1,and replacing 2-methoxy-1-methyl-ethylamine withC-(5-methyl-pyrazin-2-yl)-methylamine in step 4,N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzamidewas prepared, MS (M+H)=455.

Additional compounds prepared by the above procedure are shown in Table1.

Example 5 4′-Methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylicacid (2-methoxy-1-methyl-ethyl)-amide

The synthetic procedure used in this example is outlined below in Scheme0.

Step 1 5-Acetylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester

To a stirred solution of 5-amino-4′-methyl-biphenyl-3-carboxylic acidmethyl ester (3.672 mmol, 884.9 mg) and pyridine (36.7 mmol, 3 mL) in 8mL of dry CH₂Cl₂ was added acetic anhydride (7.3 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 hour,then diluted with ethyl acetate (150 mL). The organic layer was washedwith saturated aqueous CuSO₄ solution, brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo to give5-acetylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (quant.Yield), which was used directly in the next step.

Step 2 4′-Methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acidmethyl ester

A mixture of tetrachlorosilane (10.07 mmol, 2 mL), NaN₃ (30.21 mmol,1.96 g) and 5-acetylamino-4′-methyl-biphenyl-3-carboxylic acid methylester (3.36 mmol, 950.9 mg) in 10 ml of dry acetonitrile was stirred atroom temperature for 16 hours. The reaction mixture were poured intoice-cold aqueous Na₂CO₃ solution and extracted with ethyl acetate (100mL). The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The resulting crude4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methylester was used for next step directly (880 mg, 85% yield).

Step 3 4′-Methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid

To a stirred solution of4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methylester (1 mmol, 308 mg) in 10 ml of THF was added a solution of LiOH.H₂O(5 mmol, 210 mg) in 2 mL of water. The reaction mixture was heated toreflux for 3.5 hours and then cooled to room temperature. Solvent wasremoved under reduced pressure and the liquid residue was pH adjusted to2.0 by addition of 2N aqueous HCl solution. The mixture was extractedwith ethyl acetate and the combined ethyl acetate layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo to give4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid as whitesolid (279 mg, 95% yield).

Step 4 4′-Methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide

To a stirred solution of4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (0.3402mmol, 100 mg), HOBt (0.6804 mmol, 91.9 mg),2-methoxy-1-methyl-ethylamine (0.4083 mmol, 43 μL) and NMP (1.0206 mmol,112 μL) in CH₂Cl₂ (1 mL) and DMF (0.5 mL) was added EDCI (0.6804 mmol,130.4 mg) at room temperature, and the mixture was stirred at roomtemperature for 18 hours. The mixture was extracted with ethyl acetateand the organic layer was washed with 2N aqueous NaOH, 1 N aqueous HCl,brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by Flash column chromatography, eluting withn-hexane:ethyl acetate (4:1) to give4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid(2-methoxy-1-methyl-ethyl)-amide (white powder, 90% yield). MS(M+H)=366.

Additional compounds prepared by the above procedure are shown in Table1.

Example 63-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N—((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide

The synthetic procedure used in this example is outlined below in SchemeP.

Step 1 3-(2,2-Difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester

3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.7 g, 2.89mmol, from Preparation 2), 2,2-difluoropropionic acid (0.370 g, 2.89mmol), EDCI (4.34 mmol), and HOBt (4.34 mmol) and NMM (14.45 mmol) wereadded to 25 mL of acetonitrile. The reaction mixture was stirred at roomtemperature for 21 hours, after which the acetonitrile was removed underreduced pressure. The residue was partitioned between water and EtOAc,and the combined organic layers were washed with water, dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography (EtOAc/hexanes 35:1) to give 0.630 g of3-(2,2-difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic acidmethyl ester as a white solid, MS (M+H)=335.

Step 23-(1-Chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester

3-(2,2-Difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic acidmethyl ester (0.630 g, 1.88 mmol) and triphenyl phosphine (0.989 g, 3.77mmol) were added to 15 mL of CCl₄. The reaction mixture was heated to95° C. and stirred under nitrogen for 48 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure togive 0.612 g of3-(1-chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester, which was used directly in the next step withoutfurther purification.

Step 33-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester

3-(1-Chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester (0.611 g, 1.732 mmol) and NaN₃ (0.225 g, 3.464 mmol)were added to 10 mL acetonitrile, and the mixture was stirred at roomtemperature for 90 minutes. Solvent was removed under reduced pressureand the residue was partitioned between water and EtOAc. The combinedorganic layers were washed with water, dried (MgSO₄), filtered andconcentrated under reduced pressure to give 0.605 g of3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester as a white powder, MS (M+H)=360.

Step 43-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoicacid

3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoicacid methyl ester (0.605 g, 0.68 mmol) was added to a mixture ofmethanol (10 mL), methylene chloride (2 mL) and 3N aqueous NaOH (0.5mL). The reaction mixture was stirred at room temperature for 18 hours,then solvent was removed under reduced pressure. The liquid residue wasdiluted with water and acidified to pH 5 by addition of 1N aqueous HCl.The resulting mixture was extracted with EtOAc, and the combined organiclayers were washed with water, dried (MgSO₄), filtered and concentratedunder reduced pressure to give 0.552 g of3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoicacid.

Step 53-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N—((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide

3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoicacid was reacted with (R)-2-amino-propan-1-ol using the procedure ofstep 4 of Example 5, to afford3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N—((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide,MS (M+H)=403.

Similarly prepared, but replacing (R)-2-amino-propan-1-ol in step 4 withC-(5-methyl-pyrazin-2-yl)-methylamine, was3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide,MS (M+H)=451.

Similarly prepared, but replacing (R)-2-amino-propan-1-ol in step 4 with1-pyrazin-2-yl-ethylamine, was3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide,MS (M+H)=451.

Similarly prepared, but replacing (R)-2-amino-propan-1-ol in step 4 withcyclopropylamine, wasN-Cyclopropyl-3-[5-(1,1-difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzamide,MS (M+H)=385.

Additional compounds prepared by the above procedure are shown in Table1.

Example 73-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide

The synthetic procedure used in this example is outlined below in SchemeQ.

Step 1 3-(5-Chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methylester

3-Amino-5-(5-chloro-pyridin-2-yl)-benzoic acid methyl ester (1.5 g, 5.71mmol, from Preparation 2) and Et₃N (2.39 mL, 17.13 mmol) were dissolvedin 30 mL methylene chloride, and isobutyryl chloride (72 mL, 6.85 mmol)was added. The reaction mixture was stirred at room temperature for twohours, and then was partitioned between water and methylene chloride.The combined organic layers were dried (MgSO₄), filtered andconcentrated under reduced pressure to give 1.29 g of3-(5-chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester,MS (M+H)=333.

Step 2 3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoicacid methyl ester

3-(5-Chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester(1.90 g, 5.71 mmol) was dissolved in acetonitrile, and NaN₃ (3.71 g,5.71 mmol) and SiCl₄ (1.64 mL, 14.28 mmol) were added. The reactionmixture was stirred at 60° C. for 18 hours, then cooled and poured in tocold saturated aqueous NaHCO₃. The resulting mixture was extracted withEtOAc, and the combined organic layers were dried (MgSO₄), filtered andconcentrated under reduced pressure to give 1.84 g of3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acidmethyl ester, MS (M+H)=358.

Step 3 3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoicacid

3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acidmethyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MeOH (15mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) wasadded. The reaction mixture was stirred at room temperature for 18 hoursand then partitioned between water and 1N aqueous HCl. The combinedorganic layers were dried (MgSO₄), filtered and concentrated underreduced pressure to give 1.70 g of3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid,Mp=179.5-181.2° C., MS (M+H)=344.

Step 43-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide

3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid(650 mg, 1.89 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (233 mg, 1.89mmol), EDCI (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and Et₃N (1.32mL, 9.45 mmol) were added to 10 mL methylene chloride. The reactionmixture was stirred at room temperature for 18 hours, then waspartitioned between water and methylene chloride. The combined organiclayers were dried (MgSO₄), filtered and concentrated under reducedpressure. The resulting residue was purified via flash chromatography(80-100% EtOAc/hexanes) to give 492 mg of3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide,MS (M+H)=449.

Similarly prepared, but replacing C-(5-methyl-pyrazin-2-yl)-methylaminewith 1-pyrazin-2-yl-ethylamine in step 4, was3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide,MS (M+H)=449.

Similarly prepared, but replacing C-(5-methyl-pyrazin-2-yl)-methylaminewith 3,5-difluoro-pyridin-2-ylmethylamine in step 4, was3-(5-chloro-pyridin-2-yl)-N-(3,5-difluoro-pyridin-2-ylmethyl)-5-(5-isopropyl-tetrazol-1-yl)-benzamide,Mp=80.0-82.0° C.

Similarly prepared, but replacing C-(5-methyl-pyrazin-2-yl)-methylaminewith (S)-2-hydroxy-1-methyl-ethylamine in step 4, was3-(5-chloro-pyridin-2-yl)-N—((S)-2-hydroxy-1-methyl-ethyl)-5-(5-isopropyl-tetrazol-1-yl)-benzamide,Mp=124.0-125.0° C.

Similarly prepared, but replacing C-(5-methyl-pyrazin-2-yl)-methylaminewith cyclopropylamine in step 4, was3-(5-chloro-pyridin-2-yl)-N-cyclopropyl-5-(5-isopropyl-tetrazol-1-yl)-benzamide,Mp=107.0-108.0° C.

Similarly prepared, but replacing3-amino-5-(5-chloro-pyridin-2-yl)-benzoic acid methyl ester with3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, was3-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide,MS (M+H)=429.

Similarly prepared, but replacing isobutyryl chloride in step 1 with3-methyl-butyryl chloride, was3-(5-chloro-pyridin-2-yl)-5-(5-isobutyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide,MS (M+H)=463.

Similarly, but replacing 3-amino-5-(5-chloro-pyridin-2-yl)-benzoic acidmethyl ester with 5-amino-4′-methyl-biphenyl-3-carboxylic acid methylester in step 1, was5-(5-isopropyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid(5-methyl-pyrazin-2-ylmethyl)-amide, Mp=152-154.5° C.

Additional compounds prepared by the above procedure are shown in Table1.

Example 8 Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesiumstearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate 0.5%Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine)1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration

Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodiumchloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulatedsugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation

Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to makeisotonic Water for injection  100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation

Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 100074.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation

Ingredients Grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylatedhydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 9 P2X₃/P2X_(2/3) FLIPR (Fluorometric Imaging Plate Reader) Assay

CHO-K1 cells were transfected with cloned rat P2X₃ or human P2X_(2/3)receptor subunits and passaged in flasks. 18-24 hours before the FLIPRexperiment, cells were released from their flasks, centrifuged, andresuspended in nutrient medium at 2.5×10⁵ cells/ml. The cells werealiquoted into black-walled 96-well plates at a density of 50,000cells/well and incubated overnight in 5% CO₂ at 37° C. On the day of theexperiment, cells were washed in FLIPR buffer (calcium- andmagnesium-free Hank's balanced salt solution, 10 mM HEPES, 2 mM CaCl₂,2.5 mM probenecid; FB). Each well received 100 μl FB and 100 μl of thefluorescent dye Fluo-3 AM [2 μM final conc.]. After a 1 hour dye loadingincubation at 37° C., the cells were washed 4 times with FB, and a final75 μl/well FB was left in each well.

Test compounds (dissolved in DMSO at 10 mM and serially diluted with FB)or vehicle were added to each well (25 μl of a 4× solution) and allowedto equilibrate for 20 minutes at room temperature. The plates were thenplaced in the FLIPR and a baseline fluorescence measurement (excitationat 488 nm and emission at 510-570 nm) was obtained for 10 seconds beforea 100 μl/well agonist or vehicle addition. The agonist was a 2× solutionof α,β-meATP producing a final concentration of 1 μM (P2X₃) or 5 μM(P2X_(2/3)). Fluorescence was measured for an additional 2 minutes at 1second intervals after agonist addition. A final addition of ionomycin(5 μM, final concentration) was made to each well of the FLIPR testplate to establish cell viability and maximum fluorescence of dye-boundcytosolic calcium. Peak fluorescence in response to the addition ofα,β-meATP (in the absence and presence of test compounds) was measuredand inhibition curves generated using nonlinear regression. PPADS, astandard P2X antagonist, was used as a positive control.

Using the above assay, the compounds of Table 1 were all determined tobe active for the P2X3 receptor. Most of the compounds have an IC50between about 6.0 and about 8.8 for P2X3. Many of the compounds have anIC50 of between about 8.0 and about 8.8 for P2X3. For example,5-(5-isobutyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid((S)-2-hydroxy-1-methyl-ethyl)-amide exhibited an IC50 of about 8.8.

Using the above assay, most of the compounds of Table 1 were determinedto be active for the P2X2/3 receptor. Most of the compounds have an IC50between about 5.5 and about 8.1 for P2X2/3. Many of the compounds havean IC50 of between about 7.0 and about 8.1 for P2X2/3. For example,5-(5-ethyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid(1-pyrazin-2-yl-ethyl)-amide exhibited and IC50 of about 8.1.

Example 10 In Vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol.Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg)in alum on days 0 and 14. Mice are then challenged with aerosolized OVA(5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound ofthe invention (100 mg/kg p.o.) all starting on day 20.

Lung function is evaluated on day 23 using the Buxco system to measurePenH in response to an aerosol methacholine challenge. Mice are theneuthanized and plasma samples collected at the end of the study.

Example 11 Volume Induced Bladder Contraction Assay

Female Sprague-Dawley rats (200-300 g) were anesthetized with urethane(1.5 g/kg, sc). The animals were tracheotomized, and a carotid arteryand femoral vein were cannulated for blood pressure measurement and drugadministration, respectively. A laparotomy was performed and the ureterswere ligated and transected proximal to the ligation. The externalurethral meatus was ligated with silk suture and the urinary bladder wascannulated via the dome for saline infusion and bladder pressuremeasurement.

Following a 15-30 minute stabilization period the bladder was infusedwith room temperature saline at 100 μl/min until continuousvolume-induced bladder contractions (VIBCs) were observed. The infusionrate was then lowered to 3-5 μl/min for 30 minutes before the bladderwas drained and allowed to rest for 30 minutes. All subsequent infusionswere performed as indicated except the lower infusion rate wasmaintained for only 15 minutes instead of 30 minutes. Bladder fillingand draining cycles were repeated until the threshold volumes (TV; thevolume needed to trigger the first micturition bladder contraction)varied by less than 10% for two consecutive baselines and contractionfrequency was within 2 contractions for a 10 minute period following theslower infusion rate. Once reproducible TVs and VIBCs were establishedthe bladder was drained and the animal was dosed with drug or vehicle(0.5 ml/kg, i.v.) 3 minutes prior to the start of the next scheduledinfusion.

Example 12 Formalin Pain Assay

Male Sprague Dawley rats (180-220 g) are placed in individual Plexiglascylinders and allowed to acclimate to the testing environment for 30min. Vehicle, drug or positive control (morphine 2 mg/kg) isadministered subcutaneously at 5 ml/kg. 15 min post dosing, formalin (5%in 50 μl) is injected into plantar surface of the right hind paw using a26-gauge needle. Rats are immediately put back to the observationchamber. Mirrors placed around the chamber allow unhindered observationof the formalin-injected paw. The duration of nociphensive behavior ofeach animal is recorded by a blinded observer using an automatedbehavioral timer. Hindpaw licking and shaking/lifting are recordedseparately in 5 min bin, for a total of 60 min. The sum of time spentlicking or shaking in seconds from time 0 to 5 min is considered theearly phase, whereas the late phase is taken as the sum of seconds spentlicking or shaking from 15 to 40 min. A plasma sample is collected.

Example 13 Colon Pain Assay

Adult male Sprague-Dawley rats (350-425 g; Harlan, Indianapolis, Ind.)are housed 1-2 per cage in an animal care facility. Rats are deeplyanesthetized with pentobarbital sodium (45 mg/kg) administeredintraperitoneally. Electrodes are placed and secured into the externaloblique musculature for electromyographic (EMG) recording. Electrodeleads are tunneled subcutaneously and exteriorized at the nape of theneck for future access. After surgery, rats are housed separately andallowed to recuperate for 4-5 days prior to testing.

The descending colon and rectum are distended by pressure-controlledinflation of a 7-8 cm-long flexible latex balloon tied around a flexibletube. The balloon is lubricated, inserted into the colon via the anus,and anchored by taping the balloon catheter to the base of the tail.Colorectal distension (CRD) is achieved by opening a solenoid gate to aconstant pressure air reservoir. Intracolonic pressure is controlled andcontinuously monitored by a pressure control device. Response isquantified as the visceromotor response (VMR), a contraction of theabdominal and hindlimb musculature. EMG activity produced by contractionof the external oblique musculature is quantified using Spike2 software(Cambridge Electronic Design). Each distension trial lasts 60 sec, andEMG activity is quantified for 20 sec before distension (baseline),during 20 sec distension, and 20 sec after distention. The increase intotal number of recorded counts during distension above baseline isdefined as the response. Stable baseline responses to CRD (10, 20, 40and 80 mmHg, 20 seconds, 4 minutes apart) are obtained in conscious,unsedated rats before any treatment.

Compounds are evaluated for effects on responses to colon distensioninitially in a model of acute visceral nociception and a model of colonhypersensitivity produced by intracolonic treatment with zymosan (1 mL,25 mg/mL) instilled into the colon with a gavage needle inserted to adepth of about 6 cm. Experimental groups will consist of 8 rats each.

Acute visceral nociception: For testing effects of drug on acutevisceral nociception, 1 of 3 doses of drug, vehicle or positive control(morphine, 2.5 mg/kg) are administered after baseline responses areestablished; responses to distension are followed over the next 60-90minutes.

Visceral hypersensitivity: For testing effects of drug or vehicle afterintracolonic treatment with zymosan, intracolonic treatment is givenafter baseline responses are established. Prior to drug testing at 4hours, responses to distension are assessed to establish the presence ofhypersensitivity. In zymosan-treated rats, administration of 1 of 3doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) aregiven 4 hours after zymosan treatment and responses to distensionfollowed over the next 60-90 minutes.

Example 14 Cold allodynia in Rats with a Chronic Constriction Injury ofthe Sciatic Nerve

The effects of compounds of this invention on cold allodynia aredetermined using the chronic constriction injury (CCI) model ofneuropathic pain in rats, where cold allodynia is measured in acold-water bath with a metal-plate floor and water at a depth of 1.5-2.0cm and a temperature of 3-4° C. (Gogas, K. R. et al., Analgesia, 1997,3, 1-8).

Specifically, CCI, rats are anesthetized; the trifurcation of thesciatic nerve is located and 4 ligatures (4-0, or 5-0 chromic gut) areplaced circumferentially around the sciatic nerve proximal to thetrifurcation. The rats are then allowed to recover from the surgery. Ondays 4-7 after surgery, the rats are initially assessed for cold-inducedallodynia by individually placing the animals in the cold-water bath andrecording the total lifts of the injured paw during a 1-min period oftime: The injured paw is lifted out of the water. Paw lifts associatedwith locomotion or body repositioning are not recorded. Rats thatdisplayed 5 lifts per min or more on day 4-7 following surgery areconsidered to exhibit cold allodynia and are used in subsequent studies.In the acute studies, vehicle, reference compound or compounds of thisinvention are administered subcutaneously (s.c.) 30 min before testing.The effects of repeated administration of the compounds of thisinvention on cold allodynia are determined 14, 20 or 38 h following thelast oral dose of the following regimen: oral (p.o.) administration ofvehicle, reference or a compound of this invention at −12 h intervals(BID) for 7 days.

Example 15 Cancer Bone Pain in C3H/HeJ Mice

The effects of compounds of this invention on bone pain are determinedbetween Day 7 to Day 18 following intramedullary injection of 2472sarcoma cells into the distal femur of C3H/HeJ mice.

Specifically, NCTC 2472 tumor cells (American Type Culture Collection,ATCC), previously shown to form lytic lesions in bone afterintramedullary injection, are grown and maintained according to ATCCrecommendations. Approximately 10⁵ cells are injected directly into themedullary cavity of the distal femur in anesthetized C3H/HeJ mice.Beginning on about Day 7, the mice are assessed for spontaneousnocifensive behaviors (flinching & guarding), palpation-evokednocifensive behaviors (flinching & guarding), forced ambulatory guardingand limb use. The effects of compounds of this invention are determinedfollowing a single acute (s.c.) administration on Day 7-Day 15. Inaddition, the effects of repeated (BID) administration of compounds ofthis invention from Day 7-Day 15 are determined within 1 hour of thefirst dose on Days 7, 9, 11, 13 and 15.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-109. (canceled)
 110. A compound of formula IIc:

or a pharmaceutically acceptable salt thereof, wherein: R⁵ is:C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl;N—C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl; C₃₋₇cycloalkyl;optionally substituted phenyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl;R¹¹ is: hydrogen; C₁₋₆alkyl; C₁₋₆alkyloxy; halo; C₁₋₆haloalkyl;hetero-C₁₋₆alkyl; C₁₋₆alkylsulfonyl or cyano; R¹² is: hydrogen;C₁₋₆alkyl; C₁₋₆alkyloxy; halo; C₁₋₆haloalkyl; hetero-C₁₋₆alkyl;C₁₋₆alkylsulfonyl or cyano; and R¹³ is hydrogen, C₁₋₆alkyl,hetero-C₁₋₆alkyl, C₃₋₆-cycloalkyl or C₃₋₆cycloalkyl-C₁₋₆alkyl; or cyano.111. The compound of claim 110, wherein R¹¹ is halo or methyl.
 112. Thecompound of claim 110, wherein R¹² is hydrogen, halo or methyl.
 113. Thecompound of claim 110, wherein R¹¹ is methyl and R¹² is halo.
 114. Thecompound of claim 110, wherein R¹³ is C₁₋₆alkyl or halo-C₁₋₆haloalkyl.115. The compound of claim 110, wherein R¹³ is C₁₋₆alkyl.
 116. Thecompound of claim 110, wherein R⁵ is: hydroxymethyl; methoxymethyl;morpholin-4-ylmethyl; piperidin-1-yl methyl optionally substituted atthe 4-position with methyl, methanesulfonyl or acetyl;1,1,-dioxo-thiomorpholin-1-yl; piperidin-1-yl optionally substitutedonce or twice with a group or groups selected independently from methyl,methoxy or halo; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl;pyrazolyl; or thiazolyl; wherein the pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrazolyl and thiazolyl each may be optionally substitutedonce or twice with a group or groups selected independently from methyl,methylamino, dimethylamino and halo.
 117. The compound of claim 110,wherein R⁵ is: C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; heteroaryl, orheterocyclyl-C₁₋₆alkyl.
 117. The compound of claim 110, wherein R⁵ is:methoxymethyl; hydroxymethyl; or pyridazin-2-yl.
 118. The compound ofclaim 110, wherein R⁵ is pyridinyl, pyrimidinyl, or pyrazinyl, each ofwhich may be substituted once or twice with a group or groupsindependently selected from methyl, fluoro, chloro, amino, methylaminoor dimethylamino.
 119. The compound of claim 110, wherein R⁵ ispyridinyl, pyrimidinyl, or pyrazinyl, each of which may be substitutedonce or twice with methyl.
 120. A compound of formula IIIc:

R⁵ is: C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; pyridinyl;pyrimidinyl; or pyrazinyl; wherein the pyridinyl, pyrimidinyl, andpyrazinyl each may be substituted once or twice with methyl; R¹² ishydrogen, halo or methy; and R¹³ is C₁₋₆alkyl or halo-C₁₋₆haloalkyl.121. The compound of claim 120, wherein R¹² is halo.
 122. The compoundof claim 120, wherein R¹² is fluoro.
 123. The compound of claim 120,wherein R¹³ is C₁₋₆alkyl.
 124. The compound of claim 120, wherein R¹³ isisopropyl.
 125. The compound of claim 120, wherein R¹³ istrifluoromethyl.
 126. The compound of claim 120, wherein R⁵ ismethoxymethyl.
 127. The compound of claim 120, wherein R⁵ ishydroxymethyl.
 128. The compound of claim 120, wherein R⁵ ispyridazin-2-yl.
 129. The compound of claim 120, wherein R⁵ is5-methyl-pyrazin-2-yl.
 130. The compound2′-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylicacid ((S)-2-hydroxy-1-methyl-ethyl)-amide, or a pharmaceuticallyacceptable salt thereof.
 131. The compound2′-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylicacid (5-methyl-pyrazin-2-ylmethyl)-amide, or a pharmaceuticallyacceptable salt thereof.
 132. The compound2′-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylicacid (2-methoxy-1-methyl-ethyl)-amide, or a pharmaceutically acceptablesalt thereof.
 133. The compound5-(5-isopropyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid(2-hydroxy-1-methyl-ethyl)-amide, or a pharmaceutically acceptable saltthereof.
 134. The compound2′-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′-methyl-biphenyl-3-carboxylicacid (1-pyrazin-2-yl-ethyl)-amide, or a pharmaceutically acceptable saltthereof.
 135. A compound of formula IVc:

or a pharmaceutically acceptable salt thereof, wherein: R⁵ is: C₁₋₆alkyl; C₁₋₆ alkyloxy-C₁₋₆ alkyl; hydroxy-C₁₋₆ alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆ alkylsulfonyl-C₁₋₆ alkyl; amino-C₁₋₆alkyl; N—C₁₋₆ alkyl-amino-C₁₋₆ alkyl; N,N-di-C₁₋₆ alkyl; C₃₋₇cycloalkyl;optionally substituted phenyl; heteroaryl, or heterocyclyl-C₁₋₆ alkyl;R¹¹ is: hydrogen; C₁₋₆alkyl; alkyloxy; halo; C₁₋₆haloalkyl;hetero-C₁₋₆alkyl; C₁₋₆alkylsulfonyl or cyano; R¹² is: hydrogen;C₁₋₆alkyl; alkyloxy; halo; C₁₋₆haloalkyl; hetero-C₁₋₆ alkyl;C₁₋₆alkylsulfonyl or cyano; and R¹³ is hydrogen, C₁₋₆alkyl,hetero-C₁₋₆alkyl, C₃₋₆-cycloalkyl or C₃₋₆cycloalkyl-C₁₋₆alkyl; or cyano.